Substituted tricyclic acid derivatives as s1p1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders

ABSTRACT

The present invention relates to certain substituted tricyclic acid derivatives of Formula (I) and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. 
     
       
         
         
             
             
         
       
     
     Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1-associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn&#39;s disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, myocardial ischemia-reperfusion injury, hypertensive nephropathy, glomerulosclerosis, gastritis, polymyositis, thyroiditis, vitiligo, hepatitis, biliary cirrhosis, microbial infections and associated diseases, viral infections and associated diseases, diseases and disorders mediated by lymphocytes, auto immune diseases, inflammatory diseases, and cancer.

FIELD OF THE INVENTION

The present invention relates to certain substituted tricyclic acidderivatives of Formula (I) and pharmaceutically acceptable saltsthereof, which exhibit useful pharmacological properties, for example,as agonists of the S1P1 receptor.

Also provided by the present invention are pharmaceutical compositionscontaining compounds of the invention, and methods of using thecompounds and compositions of the invention in the treatment ofS1P1-associated disorders, for example, psoriasis, rheumatoid arthritis,Crohn's disease, transplant rejection, multiple sclerosis, systemiclupus erythematosus, ulcerative colitis, type I diabetes, acne,myocardial ischemia-reperfusion injury, hypertensive nephropathy,glomerulosclerosis, gastritis, polymyositis, thyroiditis, vitiligo,hepatitis, biliary cirrhosis, microbial infections and associateddiseases, viral infections and associated diseases, diseases anddisorders mediated by lymphocytes, auto immune diseases, inflammatorydiseases, and cancer.

BACKGROUND OF THE INVENTION

The present invention relates to compounds that are S1P1 receptoragonists having at least immunosuppressive, anti-inflammatory, and/orhemostatic activities, e.g. by virtue of modulating leukocytetrafficking, sequestering lymphocytes in secondary lymphoid tissues,and/or enhancing vascular integrity.

The present application is in part focused on addressing an unmet needfor immunosuppressive agents such as may be orally available which havetherapeutic efficacy for at least autoimmune diseases and disorders,inflammatory diseases and disorders (e.g., acute and chronicinflammatory conditions), transplant rejection, cancer, and/orconditions that have an underlying defect in vascular integrity or thatare associated with angiogenesis such as may be pathologic (e.g., as mayoccur in inflammation, tumor development, and atherosclerosis) withfewer side effects such as the impairment of immune responses tosystemic infection.

The sphingosine-1-phosphate (S1P) receptors 1-5 constitute a family of Gprotein-coupled receptors with a seven-transmembrane domain. Thesereceptors, referred to as S1P1 to S1P5 (formerly termed endothelialdifferentiation gene (EDG) receptor-1, -5, -3, -6, and -8, respectively;Chun et al., Pharmacological Reviews, 54:265-269, 2002), are activatedvia binding by sphingosine-1-phosphate, which is produced by thesphingosine kinase-catalyzed phosphorylation of sphingosine. S1P1, S1P4,and S1P5 receptors activate Gi but not Gq, whereas S1P2 and S1P3receptors activate both Gi and Gq. The S1P3 receptor, but not the S1P1receptor, responds to an agonist with an increase in intracellularcalcium.

S1P receptor agonists having agonist activity on the S1P1 receptor havebeen shown to rapidly and reversibly induce lymphopenia (also referredto as peripheral lymphocyte lowering (PLL); Hale et al., Bioorg. Med.Chem. Lett., 14:3351-3355, 2004). This is attended by clinically usefulimmunosuppression by virtue of sequestering T- and B-cells in secondarylymphoid tissue (lymph nodes and Peyer's patches) and thus apart fromsites of inflammation and organ grafts (Rosen et al., Immunol. Rev.,195:160-177, 2003; Schwab et al., Nature Immunol., 8:1295-1301, 2007).This lymphocyte sequestration, for example in lymph nodes, is thought tobe a consequence of concurrent agonist-driven functional antagonism ofthe S1P1 receptor on T-cells (whereby the ability of S1P to mobilizeT-cell egress from lymph nodes is reduced) and persistent agonism of theS1P1 receptor on lymph node endothelium (such that barrier functionopposing transmigration of lymphocytes is increased) (Matloubian et al.,Nature, 427:355-360, 2004; Baumruker et al., Expert Opin. Investig.Drugs, 16:283-289, 2007). It has been reported that agonism of the S1P1receptor alone is sufficient to achieve lymphocyte sequestration (Sannaet al., J Biol. Chem., 279:13839-13848, 2004) and that this occurswithout impairment of immune responses to systemic infection (Brinkmannet al, Transplantation, 72:764-769, 2001; Brinkmann et al., TransplantProc., 33:530-531, 2001).

That agonism of endothelial S1P1 receptors has a broader role inpromoting vascular integrity is supported by work implicating the S1P1receptor in capillary integrity in mouse skin and lung (Sanna et al.,Nat Chem. Biol., 2:434-441, 2006). Vascular integrity can be compromisedby inflammatory processes, for example as may derive from sepsis, majortrauma and surgery so as to lead to acute lung injury or respiratorydistress syndrome (Johan Groeneveld, Vascul. Pharmacol., 39:247-256,2003).

An exemplary S1P receptor agonist having agonist activity on the S1P1receptor is FTY720 (fingolimod), an immunosuppressive agent currently inclinical trials (Martini et al, Expert Opin. Investig. Drugs,16:505-518, 2007). FTY720 acts as a prodrug which is phosphorylated invivo; the phosphorylated derivative is an agonist for S1P1, S1P3, S1P4,and S1P5 receptors (but not the S1P2 receptor) (Chiba, Pharmacology &Therapeutics, 108:308-319, 2005). FTY720 has been shown to rapidly andreversibly induce lymphopenia (also referred to as peripheral lymphocytelowering (PLL); Hale et al, Bioorg. Med. Chem. Lett., 14:3351-3355,2004). This is attended by clinically useful immunosuppression by virtueof sequestering T- and B-cells in secondary lymphoid tissue (lymph nodesand Peyer's patches) and thus apart from sites of inflammation and organgrafts (Rosen et al., Immunol. Rev., 195:160-177, 2003; Schwab et al,Nature Immunol., 8:1295-1301, 2007).

In clinical trials, FTY720 elicited an adverse event (i.e., transientasymptomatic bradycardia) due to its agonism of the S1P3 receptor (Buddeet al., J. Am. Soc. Nephrol., 13:1073-1083, 2002; Sanna et al., J. Biol.Chem., 279:13839-13848, 2004; Ogawa et al., BBRC, 361:621-628, 2007).

FTY720 has been reported to have therapeutic efficacy in at least: a ratmodel for autoimmune myocarditis and a mouse model for acute viralmyocarditis (Kiyabayashi et al., J. Cardiovasc. Pharmacol., 35:410-416,2000; Miyamoto et al., J. Am. Coll. Cardiol., 37:1713-1718, 2001); mousemodels for inflammatory bowel disease including colitis (Mizushima etal., Inflamm. Bowel Dis., 10:182-192, 2004; Deguchi et al., OncologyReports, 16:699-703, 2006; Fujii et al., Am. J. Physiol. Gastrointest.Liver Physiol., 291:G267-G274, 2006; Daniel et al., J. Immunol.,178:2458-2468, 2007); a rat model for progressive mesangioproliferativeglomerulonephritis (Martini et al., Am. J. Physiol. Renal Physiol.,292:F1761-F1770, 2007); a mouse model for asthma, suggested to beprimarily through the S1P1 receptor on the basis of work using the S1P1receptor agonist SEW2871 (Idzko et al, J. Clin. Invest., 116:2935-2944,2006); a mouse model for airway inflammation and induction of bronchialhyperresponsiveness (Sawicka et al., J. Immunol., 171; 6206-6214, 2003);a mouse model for atopic dermatitis (Kohno et al., Biol. Pharm. Bull.,27:1392-1396, 2004); a mouse model for ischemia-reperfusion injury(Kaudel et al., Transplant. Proc, 39:499-502, 2007); a mouse model forsystemic lupus erythematosus (SLE) (Okazaki et al., J. Rheumatol.,29:707-716, 2002; Herzinger et al, Am. J. Clin. Dermatol., 8:329-336,2007); rat models for rheumatoid arthritis (Matsuura et al., Int. J.Immunopharmacol., 22:323-331, 2000; Matsuura et al., Inflamm. Res.,49:404-410, 2000); a rat model for autoimmune uveitis (Kurose et al.,Exp. Eye Res., 70:7-15, 2000); mouse models for type I diabetes (Fu etal, Transplantation, 73:1425-1430, 2002; Maki et al., Transplantation,74:1684-1686, 2002; Yang et al., Clinical Immunology, 107:30-35, 2003;Maki et al., Transplantation, 79:1051-1055, 2005); mouse models foratherosclerosis (Nofer et al., Circulation, 115:501-508, 2007; Keul etal., Arterioscler. Thromb. Vasc. Biol., 27:607-613, 2007); a rat modelfor brain inflammatory reaction following traumatic brain injury (TBI)(Zhang et al., J. Cell. Mol. Med., 11:307-314, 2007); and mouse modelsfor graft coronary artery disease and graft-versus-host disease (GVHD)(Hwang et al., Circulation, 100:1322-1329, 1999; Taylor et al., Blood,110:3480-3488, 2007). In vitro results suggest that FTY720 may havetherapeutic efficacy for β-amyloid-related inflammatory diseasesincluding Alzheimer's disease (Kaneider et al., FASEB J., 18:309-311,2004). KRP-203, an S1P receptor agonist having agonist activity on theS1P1 receptor, has been reported to have therapeutic efficacy in a ratmodel for autoimmune myocarditis (Ogawa et al., BBRC, 361:621-628,2007). Using the S1P1 receptor agonist SEW2871, it has been shown thatagonism of endothelial S1P1 receptors prevents proinflammatorymonocyte/endothelial interactions in type I diabetic vascularendothelium (Whetzel et al., Circ. Res., 99:731-739, 2006) and protectsthe vasculature against TNFα-mediated monocyte/endothelial interactions(Bolick et al., Arterioscler. Thromb. Vasc. Biol., 25:976-981, 2005).

Additionally, FTY720 has been reported to have therapeutic efficacy inexperimental autoimmune encephalomyelitis (EAE) in rats and mice, amodel for human multiple sclerosis (Brinkmann et al., J. Biol. Chem.,277:21453-21457, 2002; Fujino et al., J. Pharmacol. Exp. Ther.,305:70-77, 2003; Webb et al., J. Neuroimmunol., 153:108-121, 2004;Rausch et al., J. Magn. Reson. Imaging, 20:16-24, 2004; Kataoka et al.,Cellular & Molecular Immunology, 2:439-448, 2005; Brinkmann et al.,Pharmacology & Therapeutics, 115:84-105, 2007; Baumruker et al., ExpertOpin. Investig. Drugs, 16:283-289, 2007; Balatoni et al., Brain ResearchBulletin, 74:307-316, 2007). Furthermore, FTY720 has been found to havetherapeutic efficacy for multiple sclerosis in clinical trials. In PhaseII clinical trials for relapsing-remitting multiple sclerosis, FTY720was found to reduce the number of lesions detected by magnetic resonanceimaging (MRI) and clinical disease activity in patients with multiplesclerosis (Kappos et al., N Engl. J. Med., 355:1124-1140, 2006; Martiniet al., Expert Opin. Investig. Drugs, 16:505-518, 2007; Zhang et al.,Mini-Reviews in Medicinal Chemistry, 7:845-850, 2007; Brinkmann,Pharmacology & Therapeutics, 115:84-105, 2007). FTY720 is currently inPhase III studies of remitting-relapsing multiple sclerosis (Brinkmann,Pharmacology & Therapeutics, 115:84-105, 2007; Baumruker et al., Expert.Opin. Investig. Drugs, 16:283-289, 2007; Dev et al., Pharmacology andTherapeutics, 117:77-93, 2008).

Recently, FTY720 has been reported to have anti-viral activity. Specificdata has been presented in the lymphocytic choriomeningitis virus (LCMV)mouse model, wherein the mice were infected with either the Armstrong orthe clone 13 strain of LCMV (Premenko-Lanier et al., Nature, 454, 894,2008).

FTY720 has been reported to impair migration of dendritic cells infectedwith Francisella tularensis to the mediastinal lymph node, therebyreducing the bacterial colonization of it. Francisella tularensis isassociated with tularemia, ulceroglandular infection, respiratoryinfection and a typhoidal disease (E. Bar-Haim et al, PLoS Pathogens,4(11): e1000211. doi:10.1371/journal.ppat.1000211, 2008).

It has also been recently reported that a short-term high dose of FTY720rapidly reduced ocular infiltrates in experimental autoimmuneuveoretinitis. When given in the early stages of ocular inflammation,FTY720 rapidly prevented retinal damage. It was reported to not onlyprevent infiltration of target organs, but also reduce existinginfiltration (Raveney et al., Arch. Ophthalmol. 126(10), 1390, 2008).

It has been reported that treatment with FTY720 relievedovariectomy-induced osteoporosis in mice by reducing the number ofmature osteoclasts attached to the bone surface. The data providedevidence that S1P controled the migratory behaviour of osteoclastprecursors, dynamically regulating bone mineral homeostasis (Ishii etal., Nature, advance online publication, 8 Feb. 2009,doi:10.1038/nature07713).

Agonism of the S1P1 receptor has been implicated in enhancement ofsurvival of oligodendrocyte progenitor cells. Survival ofoligodendrocyte progenitor cells is a required component of theremyelination process. Remyelination of multiple sclerosis lesions isconsidered to promote recovery from clinical relapses. (Miron et al.,Ann. Neurol., 63:61-71, 2008; Coelho et al., J. Pharmacol. Exp. Ther.,323:626-635, 2007; Dev et al., Pharmacology and Therapeutics, 117:77-93,2008). It also has been shown that the S1P1 receptor plays a role inplatelet-derived growth factor (PDGF)-induced oligodendrocyte progenitorcell mitogenesis (Jung et al., Glia, 55:1656-1667, 2007).

Agonism of the S1P1 receptor has also been reported to mediate migrationof neural stem cells toward injured areas of the central nervous system(CNS), including in a rat model of spinal cord injury (Kimura et al.,Stem Cells, 25:115-124, 2007).

Agonism of the S1P1 receptor has been implicated in the inhibition ofkeratinocyte proliferation (Sauer et al., J. Biol. Chem.,279:38471-38479, 2004), consistent with reports that S1P inhibitskeratinocyte proliferation (Kim et al., Cell Signal, 16:89-95, 2004).The hyperproliferation of keratinocytes at the entrance to the hairfollicle, which can then become blocked, and an associated inflammationare significant pathogenetic factors of acne (Koreck et al.,Dermatology, 206:96-105, 2003; Webster, Cutis, 76:4-7, 2005).

FTY720 has been reported to have therapeutic efficacy in inhibitingpathologic angiogenesis, such as that as may occur in tumor development.Inhibition of angiogenesis by FTY720 is thought to involve agonism ofthe S1P1 receptor (Oo et al., J. Biol. Chem., 282; 9082-9089, 2007;Schmid et al., J. Cell Biochem., 101:259-270, 2007). FTY720 has beenreported to have therapeutic efficacy for inhibiting primary andmetastatic tumor growth in a mouse model of melanoma (LaMontagne et al.,Cancer Res., 66:221-231, 2006). FTY720 has been reported to havetherapeutic efficacy in a mouse model for metastatic hepatocellularcarcinoma (Lee et al., Clin. Cancer Res., 11:84588466, 2005).

It has been reported that oral administration of FTY720 to mice potentlyblocked VEGF-induced vascular permeability, an important processassociated with angiogenesis, inflammation, and pathological conditionssuch as sepsis, hypoxia, and solid tumor growth (T Sanchez et al, J.Biol. Chem., 278(47), 47281-47290, 2003).

Cyclosporin A and FK506 (calcineurin inhibitors) are drugs used toprevent rejection of transplanted organs. Although they are effective indelaying or suppressing transplant rejection, classicalimmunosuppressants such as cyclosporin A and FK506 are known to causeseveral undesirable side effects including nephrotoxicity,neurotoxicity, β-cell toxicity and gastrointestinal discomfort. There isan unmet need in organ transplantation for an immunosuppressant withoutthese side effects which is effective as a monotherapy or in combinationwith a classical immunosuppressant for inhibiting migration of, e.g.,alloantigen-reactive T-cells to the grafted tissue, thereby prolonginggraft survival.

FTY720 has been shown to have therapeutic efficacy in transplantrejection both as a monotherapy and in synergistic combination with aclassical immunosuppressant, including cyclosporin A, FK506 and RAD (anmTOR inhibitor). It has been shown that, unlike the classicalimmunosuppressants cyclosporin A, FK506 and RAD, FTY720 has efficacy forprolonging graft survival without inducing general immunosuppression,and this difference in drug action is believed to be relevant to thesynergism observed for the combination (Brinkmann et al., TransplantProc., 33:530-531, 2001; Brinkmann et al., Transplantation, 72:764-769,2001).

Agonism of the S1P1 receptor has been reported to have therapeuticefficacy for prolonging allograft survival in mouse and rat skinallograft models (Lima et al., Transplant Proc., 36:1015-1017, 2004; Yanet al., Bioorg. & Med. Chem. Lett., 16:3679-3683, 2006). FTY720 has beenreported to have therapeutic efficacy for prolonging allograft survivalin a rat cardiac allograft model (Suzuki et al., Transpl. Immunol.,4:252-255, 1996). FTY720 has been reported to act synergistically withcyclosporin A to prolong rat skin allograft survival (Yanagawa et al.,J. Immunol., 160:5493-5499, 1998), to act synergistically withcyclosporin A and with FK506 to prolong rat cardiac allograft survival,and to act synergistically with cyclosporin A to prolong canine renalallograft survival and monkey renal allograft survival (Chiba et al.,Cell Mol Biol., 3:11-19, 2006). KRP-203, an S1P receptor agonist hasbeen reported to have therapeutic efficacy for prolonging allograftsurvival in a rat skin allograft model and both as monotherapy and insynergistic combination with cyclosporin A in a rat cardiac allograftmodel (Shimizu et al., Circulation, 111:222-229, 2005). KRP-203 also hasbeen reported to have therapeutic efficacy in combination withmycophenolate mofetil (MMF; a prodrug for which the active metabolite ismycophenolic acid, an inhibitor of purine biosynthesis) for prolongingallograft survival both in a rat renal allograft model and in a ratcardiac allograft model (Suzuki et al., J Heart Lung Transplant,25:302-209, 2006; Fujishiro et al., J. Heart Lung Transplant,25:825-833, 2006). It has been reported that an agonist of the S1P1receptor, AUY954, in combination with a subtherapeutic dose of RAD001(Certican/Everolimus, an mTOR inhibitor) can prolong rat cardiacallograft survival (Pan et al., Chemistry & Biology, 13:1227-1234,2006). In a rat small bowel allograft model, FTY720 has been reported toact synergistically with cyclosporin A to prolong small bowel allograftsurvival (Sakagawa et al., Transpl. Immunol., 13:161-168, 2004). FTY720has been reported to have therapeutic efficacy in a mouse islet graftmodel (Fu et al., Transplantation, 73:1425-1430, 2002; Liu et al.,Microsurgery, 27:300-304; 2007) and in a study using human islet cellsto evidence no detrimental effects on human islet function (Truong etal., American Journal of Transplantation, 7:2031-2038, 2007).

FTY720 has been reported to reduce the nociceptive behavior in thespared nerve injury model for neuropathic pain which does not depend onprostaglandin synthesis (O. Costu et al, Journal of Cellular andMolecular Medicine 12(3), 995-1004, 2008).

FTY720 has been reported to impair initiation of murine contacthypersensitivity (CHS). Adoptive transfer of immunized lymph node cellsfrom mice treated with FTY720 during the sensitization phase wasvirtually incapable of inducing CHS response in recipients (D. Nakashimaet al., J. Investigative Dermatology (128(12), 2833-2841, 2008).

It has been reported that prophylactic oral administration of FTY720 (1mg/kg, three times a week), completely prevented the development ofexperimental autoimmune myasthenia gravis (EAMG) in C57BL/6 mice (T.Kohono et al, Biological & Pharmaceutical Bulletin, 28(4), 736-739,2005).

In one embodiment, the present invention encompasses compounds which areagonists of the S1P1 receptor having selectivity over the S1P3 receptor.The S1P3 receptor, and not the S1P1 receptor, has been directlyimplicated in bradycardia (Sanna et al., J. Biol. Chem.,279:13839-13848, 2004). An S1P1 receptor agonist selective over at leastthe S1P3 receptor has advantages over current therapies by virtue of anenhanced therapeutic window, allowing better tolerability with higherdosing and thus improving efficacy as therapy. The present inventionencompasses compounds which are agonists of the S1P1 receptor and whichexhibit no or substantially no activity for bradycardia.

S1P1 receptor agonists are useful to treat or prevent conditions wheresuppression of the immune system or agonism of the S1P1 receptor is inorder, such as diseases and disorders mediated by lymphocytes,transplant rejection, autoimmune diseases and disorders, inflammatorydiseases and disorders, and conditions that have an underlying defect invascular integrity or that relate to angiogenesis such as may bepathologic.

In one embodiment, the present invention encompasses compounds which areagonists of the S1P1 receptor having good overall physical propertiesand biological activities and having an effectiveness that issubstantially at least that of prior compounds with activity at the S1P1receptor.

Citation of any reference throughout this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

SUMMARY OF THE INVENTION

The present invention encompasses compounds of Formula (I) andpharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein:

m is 1 or 2;

n is 1 or 2;

Y is N or CR¹;

Z is N or CR⁴;

W is N or CR⁵;

R^(a) is H or C₁-C₆ alkyl;

R¹, R², R³, and R⁴ are each independently selected from the groupconsisting of H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, carboxamide, cyano, C₃-C₇ cycloalkoxy,C₃-C₇ cycloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen,heteroaryl, and heterocyclyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxyare each optionally substituted with one C₃-C₇ cycloalkyl group; and

R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆alkylsulfonyl, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen,heteroaryl, and heterocyclyl.

One aspect of the present invention pertains to compounds of Formula(Ia) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

m is 1 or 2;

n is 1 or 2;

Y is N or CR¹;

Z is N or CR⁴;

W is N or CR⁵;

R¹, R², R³, and R⁴ are each independently selected from the groupconsisting of H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, carboxamide, cyano, C₃-C₇ cycloalkoxy,C₃-C₇ cycloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen,heteroaryl, and heterocyclyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxyare each optionally substituted with one C₃-C₇ cycloalkyl group; and

R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, cyano, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, halogen, and heterocyclyl.

The present invention encompasses compounds which are S1P1 receptoragonists having at least immunosuppressive, anti-inflammatory and/orhemostatic activities, e.g. by virtue of modulating leukocytetrafficking, sequestering lymphocytes in secondary lymphoid tissues,and/or enhancing vascular integrity.

S1P1 receptor agonists are useful to treat or prevent conditions wheresuppression of the immune system or agonism of the S1P1 receptor is inorder, such as diseases and disorders mediated by lymphocytes,transplant rejection, autoimmune diseases and disorders, inflammatorydiseases and disorders (e.g., acute and chronic inflammatoryconditions), cancer, and conditions that have an underlying defect invascular integrity or that are associated with angiogenesis such as maybe pathologic (e.g., as may occur in inflammation, tumor development andatherosclerosis). Such conditions where suppression of the immune systemor agonism of the S1P1 receptor is in order include diseases anddisorders mediated by lymphocytes, conditions that have an underlyingdefect in vascular integrity, autoimmune diseases and disorders,inflammatory diseases and disorders (e.g., acute and chronicinflammatory conditions), acute or chronic rejection of cells, tissue orsolid organ grafts, arthritis including psoriatic arthritis andrheumatoid arthritis, diabetes including type I diabetes, demyelinatingdisease including multiple sclerosis, ischemia-reperfusion injuryincluding renal and cardiac ischemia-reperfusion injury, inflammatoryskin disease including psoriasis, atopic dermatitis and acne,hyperproliferative skin disease including acne, inflammatory boweldisease including Crohn's disease and ulcerative colitis, systemic lupuserythematosis, asthma, uveitis, myocarditis, allergy, atherosclerosis,brain inflammation including Alzheimer's disease and brain inflammatoryreaction following traumatic brain injury, central nervous systemdisease including spinal cord injury or cerebral infarction, pathologicangiogenesis including as may occur in primary and metastatic tumorgrowth, rheumatoid arthritis, diabetic retinopathy and atherosclerosis,cancer, chronic pulmonary disease, acute lung injury, acute respiratorydisease syndrome, sepsis, and the like.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a compound of the present invention and apharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for treating adisorder associated with the S1P1 receptor in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating anS1P1 receptor-associated disorder in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating adisease or disorder mediated by lymphocytes in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating anautoimmune disease or disorder in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treating aninflammatory disease or disorder in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating amicrobial or viral infection or disease in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treatingcancer in an individual comprising administering to the individual inneed thereof a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating anS1P1 receptor-associated disorder in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof, wherein the disorder is selectedfrom the group consisting of psoriasis, rheumatoid arthritis, Crohn'sdisease, transplant rejection, multiple sclerosis, systemic lupuserythematosus, ulcerative colitis, type I diabetes, hypertensivenephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury,and acne.

One aspect of the present invention pertains to methods for treating adisorder in an individual comprising administering to the individual inneed thereof a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof, wherein thedisorder is selected from the group consisting of psoriasis, rheumatoidarthritis, Crohn's disease, transplant rejection, multiple sclerosis,systemic lupus erythematosus, ulcerative colitis, type I diabetes, andacne.

One aspect of the present invention pertains to methods for treatingpsoriasis in an individual comprising administering to the individual inneed thereof a therapeutically effective amount of a compound of thepresent invention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treatingrheumatoid arthritis in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingCrohn's disease in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingtransplant rejection in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingmultiple sclerosis in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingsystemic lupus erythematosus in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingulcerative colitis in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingtype I diabetes in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatinghypertensive nephropathy in an individual comprising administering tothe individual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingglomerulosclerosis in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositionthereof.

One aspect of the present invention pertains to methods for treatingmyocardial ischemia-reperfusion injury in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound of the present invention or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treatingacne in an individual comprising administering to the individual in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of an S1P 1 receptor-associated disorder.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of an S1P1 receptor-associated disorder selected from thegroup consisting of psoriasis, rheumatoid arthritis, Crohn's disease,transplant rejection, multiple sclerosis, systemic lupus erythematosus,ulcerative colitis, type I diabetes, hypertensive nephropathy,glomerulosclerosis, myocardial ischemia-reperfusion injury, and acne.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of a disease or disorder mediated by lymphocytes.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of an autoimmune disease or disorder.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of an inflammatory disease or disorder.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of a microbial or viral infection or disease.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of cancer.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of an S1P1 receptor-associated disorder selected from thegroup consisting of psoriasis, rheumatoid arthritis, Crohn's disease,transplant rejection, multiple sclerosis, systemic lupus erythematosus,ulcerative colitis, type I diabetes, and acne.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of psoriasis.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of rheumatoid arthritis.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of Crohn's disease.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of transplant rejection.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of multiple sclerosis.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of systemic lupus erythematosus.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of ulcerative colitis.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of type I diabetes.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of hypertensive nephropathy.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of glomerulosclerosis.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of myocardial ischemia-reperfusion injury.

One aspect of the present invention pertains to the use of compounds ofthe present invention in the manufacture of a medicament for thetreatment of acne.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of the human or animalbody by therapy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of an S1P1receptor-associated disorder selected from the group consisting ofpsoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus, ulcerative colitis,type I diabetes, hypertensive nephropathy, glomerulosclerosis,myocardial ischemia-reperfusion injury, and acne.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of an S1P1receptor-associated disorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of a disease or disordermediated by lymphocytes.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of an autoimmune diseaseor disorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of an inflammatorydisease or disorder.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of a microbial or viralinfection or disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of cancer.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of an S1P1receptor-associated disorder selected from the group consisting ofpsoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus, ulcerative colitis,type I diabetes, and acne.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of psoriasis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of rheumatoid arthritis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of Crohn's disease.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of transplant rejection.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of multiple sclerosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of systemic lupuserythematosus.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of ulcerative colitis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of type I diabetes.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of hypertensivenephropathy.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of glomerulosclerosis.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of myocardialischemia-reperfusion injury.

One aspect of the present invention pertains to compounds of the presentinvention for use in a method for the treatment of acne.

One aspect of the present invention pertains to processes for preparinga composition comprising admixing a compound of the present inventionand a pharmaceutically acceptable carrier.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a general synthetic scheme for the preparation of2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetatederivatives, as intermediates useful in the preparation of compounds ofFormula (I), by treatment of ethyl 5-bromo-1H-indole-2-carboxylate withbutyl acrylate and subsequent decarboxylation, followed by olefination,conversion of the bromo group to a hydroxyl group and reduction of thedouble bond.

FIG. 2 shows a general synthetic scheme for the preparation of2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetatederivatives, as intermediates useful in the preparation of compounds ofFormula (I), by treatment of ethyl 5-(benzyloxy)-1H-indole-2-carboxylatewith butyl acrylate and subsequent decarboxylation, followed byolefination and reduction/deprotection.

FIG. 3 shows a general synthetic scheme for the preparation of2-(6-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetatederivatives, as intermediates useful in the preparation of compounds ofFormula (I), by alkylation of tert-butyl 2-oxopyrrolidine-1-carboxylate,followed by N-arylation, reduction/deprotection and cyclization.

FIG. 4 shows a general synthetic scheme for the preparation of tricyclicacid derivatives, via coupling of the aryl methyl halides or alcoholswith 2,3-dihydro-1H-pyrrolo acetate derivatives. Subsequent deprotectionand/or halogenation afford compounds of Formula (I).

FIG. 5 shows a general synthetic scheme for the preparation of tricyclicacid derivatives, via iodination of tricyclic ester derivatives.Subsequent metal-catalyzed coupling reaction and deprotection affordcompounds of Formula (I).

FIG. 6 shows a general synthetic scheme for the preparation of2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetatederivatives, as intermediates useful in the preparation of compounds ofFormula (Ia), by treatment of ethyl 5-bromo-1H-indole-2-carboxylate withbutyl acrylate and subsequent decarboxylation, followed by olefination,conversion of the bromo group to a hydroxyl group and reduction of thedouble bond.

FIG. 7 shows a general synthetic scheme for the preparation of2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetatederivatives, as intermediates useful in the preparation of compounds ofFormula (Ia), by treatment of ethyl5-(benzyloxy)-1H-indole-2-carboxylate with butyl acrylate and subsequentdecarboxylation, followed by olefination and reduction/deprotection.

FIG. 8 shows a general synthetic scheme for the preparation of2-(6-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetatederivatives, as intermediates useful in the preparation of compounds ofFormula (Ia), by alkylation of tert-butyl2-oxopyrrolidine-1-carboxylate, followed by N-arylation,reduction/deprotection and cyclization.

FIG. 9 shows a general synthetic scheme for the preparation of tricyclicacid derivatives, via coupling of the aryl methyl halides or alcoholswith 2,3-dihydro-1H-pyrrolo acetate derivatives. Subsequent deprotectionand/or halogenation afford compounds of Formula (Ia).

FIG. 10 shows a general synthetic scheme for the preparation oftricyclic acid derivatives, via iodination of tricyclic esterderivatives. Subsequent metal-catalyzed coupling reaction anddeprotection afford compounds of Formula (Ia).

FIG. 11 shows the results of an experiment which measured the ability ofCompound 2 to lower the absolute count of peripheral lymphocytes in micecompared to vehicle.

FIG. 12 shows the results of an experiment which measured the ability ofthe 1^(st) enantiomer of Compound 12 (isolated after resolution ofcompound 12 by HPLC, with a retention time of 15 min per the conditionsreported in Example 1.3) to lower the absolute count of peripherallymphocytes in rats compared to vehicle.

FIG. 13 shows the results of an experiment which measured the ability ofthe 2^(nd) enantiomer of Compound 12 (isolated after resolution ofcompound 12 by HPLC, with a retention time of 18 min per the conditionsreported in Example 1.3) to lower the absolute count of peripherallymphocytes in rats compared to vehicle.

FIG. 14 shows the results of an experiment which measured the ability ofthree different doses of the 2^(nd) enantiomer of Compound 12 (isolatedafter resolution of compound 12 by HPLC, with a retention time of 18 minper the conditions reported in Example 1.3) to reduce the mean anklediameter in rats compared to vehicle.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “agonist” is intended to mean a moiety that interacts with andactivates a G-protein-coupled receptor, such as the S1P1 receptor, suchas can thereby initiate a physiological or pharmacological responsecharacteristic of that receptor. For example, an agonist activites anintracellular response upon binding to the receptor, or enhances GTPbinding to a membrane. In certain embodiments, an agonist of theinvention is an S1P1 receptor agonist that is capable of facilitatingsustained S1P1 receptor internalization (see e.g., Matloubian et al.,Nature, 427, 355, 2004).

The term “antagonist” is intended to mean a moietiy that competitivelybinds to the receptor at the same site as an agonist (for example, theendogenous ligand), but which does not activate the intracellularresponse initiated by the active form of the receptor and can therebyinhibit the intracellular responses by an agonist or partial agonist. Anantagonist does not diminish the baseline intracellular response in theabsence of an agonist or partial agonist.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably to mean a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” is intended to mean any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates and most preferably humans.

The term “inverse agonist” is intended to mean a moiety that binds tothe endogenous form of the receptor or to the constitutively activatedform of the receptor and which inhibits the baseline intracellularresponse initiated by the active form of the receptor below the normalbase level of activity which is observed in the absence of an agonist orpartial agonist, or decreases GTP binding to a membrane. In someembodiments, the baseline intracellular response is inhibited in thepresence of the inverse agonist by at least 30%. In some embodiments,the baseline intracellular response is inhibited in the presence of theinverse agonist by at least 50%. In some embodiments, the baselineintracellular response is inhibited in the presence of the inverseagonist by at least 75%, as compared with the baseline response in theabsence of the inverse agonist.

The term “modulate or modulating” is intended to mean an increase ordecrease in the amount, quality, response or effect of a particularactivity, function or molecule.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited to,salts, solvates, and hydrates of compounds of the present invention,whereby the composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The term “therapeutically effective amount” is intended to mean theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, caregiver or by an individual, which includesone or more of the following:

(1) Preventing the disease, for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease, for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease, for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Chemical Group, Moiety or Radical

The term “C₁-C₆ alkoxy” is intended to mean a C₁-C₆ alkyl radical, asdefined herein, attached directly to an oxygen atom. Some embodimentsare 1 to 5 carbons, some embodiments are 1 to 4 carbons, someembodiments are 1 to 3 carbons and some embodiments are 1 or 2 carbons.Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, isobutoxy, sec-butoxy, and the like.

The term “C₁-C₆ alkyl” is intended to mean a straight or branched carbonradical containing 1 to 6 carbons. Some embodiments are 1 to 5 carbons,some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbonsand some embodiments are 1 or 2 carbons.

Examples of an alkyl include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl,isopentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl,and the like.

The term “C₁-C₆ alkylamino” is intended to mean one alkyl radicalattached to an —NH-radical wherein the alkyl radical has the samemeaning as described herein. Some examples include, but are not limitedto, methylamino, ethylamino, n-propylamino, isopropylamino,n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, and thelike.

The term “C₁-C₆ alkylsulfonyl” is intended to mean a C₁-C₆ alkyl radicalattached to the sulfur of a sulfone radical having the formula: —S(O)₂—wherein the alkyl radical has the same definition as described herein.Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,isobutylsulfonyl, tert-butylsulfonyl, and the like.

The term “C₁-C₆ alkylthio” is intended to mean a C₁-C₆ alkyl radicalattached to a sulfur atom (i.e., —S—) wherein the alkyl radical has thesame definition as described herein. Examples include, but are notlimited to, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl,n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,isobutylsulfanyl, t-butylsulfanyl, and the like.

The term “carboxamide” is intended to mean the group —CONH₂.

The term “cyano” is intended to mean the group —CN.

The term “C₃-C₇ cycloalkoxy” is intended to mean a saturated ringradical containing 3 to 7 carbons directly bonded to an oxygen atom.Some examples include cyclopropyl-O—, cyclobutyl-O—, cyclopentyl-O—,cyclohexyl-O—, and the like.

The term “C₃-C₇ cycloalkyl” is intended to mean a saturated ring radicalcontaining 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Someembodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7carbons. Some embodiments contain 3 to 4 carbons. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike.

The term “C₁-C₆ haloalkoxy” is intended to mean a C₁-C₆ haloalkyl, asdefined herein, which is directly attached to an oxygen atom. Examplesinclude, but are not limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

The term “C₁-C₆ haloalkyl” is intended to mean an C₁-C₆ alkyl group,defined herein, wherein the alkyl is substituted with between onehalogen up to fully substituted wherein a fully substituted C₁-C₆haloalkyl can be represented by the formula C_(z)L_(2z+1) wherein L is ahalogen and “z” is 1, 2, 3, 4, 5 or 6. When more than one halogen ispresent, the halogens may be the same or different and selected from thegroup consisting of fluoro, chloro, bromo or iodo, preferably fluoro.Some embodiments are 1 to 5 carbons, some embodiments are 1 to 4carbons, some embodiments are 1 to 3 carbons and some embodiments are 1or 2 carbons. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl, and the like.

The term “halogen” or “halo” is intended to mean a fluoro, chloro, bromoor iodo group.

The term “heteroaryl” is intended to mean an aromatic ring systemcontaining 5 to 14 aromatic ring atoms that may be a single ring, twofused rings or three fused rings, wherein at least one aromatic ringatom is a heteroatom selected from, for example, but not limited to, thegroup consisting of O, S, and N wherein the N can be optionallysubstituted with H, acyl or C₁-C₄ alkyl. Some embodiments contain 5 to 6ring atoms, for example, furanyl, thienyl, pyrrolyl, imidazolyl,oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, and the like. Some embodiments contain 8 to 14 ring atoms,for example, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl,isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl,benzothienyl, benzofuranyl, isobenzofuran, and the like.

The term “heterocyclic” or “heterocyclyl” is intended to mean anon-aromatic ring containing 3 to 8 ring atoms wherein one, two or threering atoms are heteroatoms selected from, for example, the groupconsisting of O, S, S(═O), S(═O)₂, and NH, wherein the N is optionallysubstituted as described herein. In some embodiments, the nitrogen isoptionally substituted with C₁-C₄ acyl or C₁-C₄ alkyl. In someembodiments, ring carbon atoms are optionally substituted with oxo thusforming a carbonyl group. In some embodiments, ring sulfur atoms areoptionally substituted with oxo atoms thus forming a thiocarbonyl group.The heterocyclic group can be attached/bonded to any available ringatom, for example, ring carbon, ring nitrogen, and the like. In someembodiments the heterocyclic group is a 3-, 4-, 5-, 6- or 7-memberedring. Examples of a heterocyclic group include, but are not limited to,aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl,azetidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,piperzin-1-yl, piperzin-2-yl, piperzin-3-yl, piperzin-4-yl,pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl,thiomorpholin-4-yl, [1,4]oxazepan-4-yl, 1,1-dioxothiomorpholin-4-yl,azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, and the like.

Compounds of the Invention

One aspect of the present invention pertains to certain compounds ofFormula (I) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein:

m, n, R^(a), R², R³, W, Y, and Z have the same definitions as describedherein, supra and infra.

One aspect of the present invention pertains to compounds of Formula(Ia) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

m is 1 or 2;

n is 1 or 2;

Y is N or CR¹;

Z is N or CR⁴;

W is N or CR⁵;

R¹, R², R³, and R⁴ are each independently selected from the groupconsisting of H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆alkylsulfonyl, C₁-C₆ alkylthio, carboxamide, cyano, C₃-C₇ cycloalkoxy,C₃-C₇ cycloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen,heteroaryl, and heterocyclyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxyare each optionally substituted with one C₃-C₇ cycloalkyl group; and

R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, cyano, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, halogen, and heterocyclyl.

It is understood that the present invention embraces compounds, solvatesand/or hydrates of compounds, pharmaceutically acceptable salts ofcompounds, and solvates and/or hydrates of pharmaceutically acceptablesalts of compounds, wherein the compounds are as described herein.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g. m,n, R^(a), R¹, R², R³, R⁴, R⁵, R⁶, W, Y, Z, etc.) contained within thegeneric chemical formulae described herein, for example, (e.g. I, Ia,Ic, Ic, Ig, Ii, Ij, Ik, Im, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, IIi,etc.) are specifically embraced by the present invention just as if eachand every combination was individually explicitly recited, to the extentthat such combinations embrace stable compounds (i.e., compounds thatcan be isolated, characterized and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables, as well as all subcombinations ofuses and medical indications described herein, are also specificallyembraced by the present invention just as if each and everysubcombination of chemical groups and subcombination of uses and medicalindications was individually and explicitly recited herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup. The non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valence of substitution, for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one substituent, the substituents can beidentical or they can be different.

Compounds of the invention also include tautomeric forms, such asketo-enol tautomers and the like. Tautomeric forms can be in equilibriumor sterically locked into one form by appropriate substitution. It isunderstood that the various tautomeric forms are within the scope of thecompounds of the present invention.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates and/or final compounds. Isotopes include thoseatoms having the same atomic number but different mass numbers. Forexample, isotopes of hydrogen include deuterium and tritium.

It is understood and appreciated that compounds of Formula (I) and (Ia),and formulae related thereto, may have one or more chiral centers andtherefore can exist as enantiomers and/or diastereomers. The inventionis understood to extend to and embrace all such enantiomers,diastereomers and mixtures thereof, including but not limited toracemates. It is understood that Formula (I) and (Ia), and formulae usedthroughout this disclosure, are intended to represent all individualenantiomers and mixtures thereof, unless stated or shown otherwise.

The Variable “n”

In some embodiments, n is 1.

In some embodiments, compounds of the present invention are representedby Formula (Ic) as illustrated below:

wherein each variable in Formula (Ic) has the same meaning as describedherein, supra and infra.

In some embodiments, n is 2.

In some embodiments, compounds of the present invention are representedby Formula (Ie) as illustrated below:

wherein each variable in Formula (Ie) has the same meaning as describedherein, supra and infra.The Variable “m”

In some embodiments, m is 1.

In some embodiments, compounds of the present invention are representedby Formula (Ig) as illustrated below:

wherein each variable in Formula (Ig) has the same meaning as describedherein, supra and infra.

In some embodiments, m is 2.

In some embodiments, compounds of the present invention are representedby Formula (Ii) as illustrated below:

wherein each variable in Formula (II) has the same meaning as describedherein, supra and infra.

The Variables Y, Z and W

In some embodiments, Y is N or CR¹, Z is N or CR⁴, and W is N or CR⁵.

In some embodiments, Y is N, Z is N, and W is N.

In some embodiments, Y is N, Z is N, and W is CR⁵.

In some embodiments, Y is N, Z is CR⁴, and W is N.

In some embodiments, Y is CR¹, Z is N, and W is N.

In some embodiments, Y is N, Z is CR⁴, and W is CR⁵.

In some embodiments, Y is CR¹, Z is N, and W is CR⁵.

In some embodiments, Y is CR¹, Z is CR⁴, and W is N.

In some embodiments, Y is CR¹, Z is CR⁴, and W is CR⁵.

In some embodiments, Y is N.

In some embodiments, Y is CR¹.

In some embodiments, Z is N.

In some embodiments, Z is CR⁴.

In some embodiments, W is N.

In some embodiments, W is CR⁵.

The Group R^(a)

In some embodiments, R^(a) is H or C₁-C₆ alkyl.

In some embodiments, R^(a) is H or methyl.

In some embodiments, R^(a) is H.

The Group R¹

In some embodiments, R¹ is selected from the group consisting of H,C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, carboxamide, cyano, C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl,C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, andheterocyclyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are eachoptionally substituted with one C₃-C₇ cycloalkyl group.

In some embodiments, R¹ is H or C₁-C₆ haloalkyl.

In some embodiments, R¹ is H or trifluoromethyl.

In some embodiments, R¹ is H.

In some embodiments, R¹ is trifluoromethyl.

The Group R²

In some embodiments, R² is selected from the group consisting of H,C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, carboxamide, cyano, C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl,C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, andheterocyclyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are eachoptionally substituted with one C₃-C₇ cycloalkyl group.

In some embodiments, R² is selected from the group consisting of H,C₁-C₆ alkoxy, cyano, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyl,and halogen.

In some embodiments, R² is selected from the group consisting of cyano,C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl.

In some embodiments, R² is selected from the group consisting of H,chloro, cyano, ethoxy, trifluoromethoxy, and trifluoromethyl.

In some embodiments, R² is selected from the group consisting of cyano,trifluoromethoxy, and trifluoromethyl.

In some embodiments, R² is cyano.

In some embodiments, R² is trifluoromethoxy.

In some embodiments, R² is trifluoromethyl.

In some embodiments, R² is chloro.

In some embodiments, R² is ethoxy.

The Group R³

In some embodiments, R³ is selected from the group consisting of H,C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, carboxamide, cyano, C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl,C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, andheterocyclyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are eachoptionally substituted with one C₃-C₇ cycloalkyl group.

In some embodiments, R³ is selected from the group consisting of H,C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, carboxamide, cyano,C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl,halogen, and heteroaryl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy areeach optionally substituted with one C₃-C₇ cycloalkyl group.

In some embodiments, R³ is selected from the group consisting of H,C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, carboxamide, cyano,C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl, C₁-C₆ haloalkoxy, and halogen,wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are each optionally substitutedwith one C₃-C₇ cycloalkyl group.

In some embodiments, R³ is selected from the group consisting of H,C₁-C₆ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl.

In some embodiments, R³ is selected from the group consisting of H,chloro, carboxamide, cyano, cyclohexyl, cyclohexylmethyl,cyclopentyloxy, cyclopentyl, cyclopropylmethoxy,1,3-difluoropropan-2-yloxy, ethoxy, fluoromethoxy, isobutyl, isopropoxy,methoxy, methylsulfonyl, pyrazolyl, and trifluoromethyl.

In some embodiments, R³ is selected from the group consisting of H,chloro, carboxamide, cyano, cyclohexyl, cyclohexylmethyl,cyclopentyloxy, cyclopentyl, cyclopropylmethoxy,1,3-difluoropropan-2-yloxy, ethoxy, fluoromethoxy, isobutyl, isopropoxy,methoxy, and methylsulfonyl.

In some embodiments, R³ is selected from the group consisting of H,cyclohexyl, cyclopentyl, isobutyl, and isopropoxy.

In some embodiments, R³ is H.

In some embodiments, R³ is chloro.

In some embodiments, R³ is carboxamide.

In some embodiments, R³ is cyano.

In some embodiments, R³ is cyclohexyl.

In some embodiments, R³ is cyclohexylmethyl.

In some embodiments, R³ is cyclopentyloxy.

In some embodiments, R³ is cyclopentyl.

In some embodiments, R³ is cyclopropylmethoxy.

In some embodiments, R³ is 1,3-difluoropropan-2-yloxy.

In some embodiments, R³ is ethoxy.

In some embodiments, R³ is fluoromethoxy.

In some embodiments, R³ is isobutyl.

In some embodiments, R³ is isopropoxy.

In some embodiments, R³ is methoxy.

In some embodiments, R³ is methylsulfonyl.

In some embodiments, R³ is trifluoromethyl.

In some embodiments, R³ is pyrazolyl.

The Group R⁴

In some embodiments, R⁴ is selected from the group consisting of H,C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, C₁-C₆alkylthio, carboxamide, cyano, C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl,C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, andheterocyclyl, wherein the C₁-C₆ alkyl and C₁-C₆ alkoxy are eachoptionally substituted with one C₃-C₇ cycloalkyl group.

In some embodiments, R⁴ is selected from the group consisting of H,cyano, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy.

In some embodiments, R⁴ is selected from the group consisting of H,cyano, trifluoromethoxy, and trifluoromethyl.

In some embodiments, R⁴ is H or cyano.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is cyano.

The Group R⁵

In some embodiments, R⁵ is selected from the group consisting of H,C₁-C₆ alkyl, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen,heteroaryl, and heterocyclyl.

In some embodiments, R⁵ is selected from the group consisting of H,C₁-C₆ alkyl, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen,heteroaryl, and heterocyclyl.

In some embodiments, R⁵ is selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, C₃-C₇ cycloalkyl, halogen, andheteroaryl.

In some embodiments, R⁵ is selected from the group consisting of H,C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and halogen.

In some embodiments, R⁵ is selected from the group consisting of H,bromo, chloro, cyclobutyl, cyclopropyl, ethyl, fluoro, iodo, methyl,methylsulfonyl, and pyridin-2-yl.

In some embodiments, R⁵ is selected from the group consisting of H,bromo, chloro, cyclobutyl, cyclopropyl, fluoro, iodo, and methyl.

In some embodiments, R⁵ is H.

In some embodiments, R⁵ is bromo.

In some embodiments, R⁵ is chloro.

In some embodiments, R⁵ is cyclobutyl.

In some embodiments, R⁵ is cyclopropyl.

In some embodiments, R⁵ is ethyl.

In some embodiments, R⁵ is fluoro.

In some embodiments, R⁵ is iodo.

In some embodiments, R⁵ is methyl.

In some embodiments, R⁵ is methylsulfonyl.

In some embodiments, R⁵ is pyridin-2-yl.

Certain Combinations

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Ia) and pharmaceutically acceptable salts,solvates, and hydrates thereof, wherein:

m is 1 or 2;

n is 1 or 2;

Y is N or CR¹;

Z is N or CR⁴;

W is N or CR⁵;

R¹ is H;

R² is selected from the group consisting of cyano, C₁-C₆haloalkoxy, andC₁-C₆ haloalkyl;

R³ is selected from the group consisting of H, C₁-C₆ alkoxy, C₁-C₆alkyl, and C₃-C₇ cycloalkyl;

R⁴ is H or cyano; and

R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, and halogen.

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Ia) and pharmaceutically acceptable salts,solvates, and hydrates thereof, wherein:

m is 1 or 2;

n is 1 or 2;

Y is N or CR¹;

Z is N or CR⁴;

W is N or CR⁵;

R¹ is H;

R² is selected from the group consisting of cyano, trifluoromethoxy, andtrifluoromethyl;

R³ is selected from the group consisting of H, cyclohexyl, cyclopentyl,isobutyl, and isopropoxy;

R⁴ is H or cyano; and

R⁵ is selected from the group consisting of H, bromo, chloro,cyclobutyl, cyclopropyl, fluoro, iodo, and methyl.

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Ij) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein:

m is 1 or 2;

R¹ is H or C₁-C₆ haloalkyl;

R² is selected from the group consisting of H, C₁-C₆ alkoxy, cyano,C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyl, and halogen;

R³ is selected from the group consisting of H, C₁-C₆ alkoxy, C₁-C₆alkyl, C₁-C₆ alkylsulfonyl, carboxamide, cyano, C₃-C₇ cycloalkoxy, C₃-C₇cycloalkyl, C₁-C₆ haloalkoxy, and halogen, wherein the C₁-C₆ alkyl andC₁-C₆ alkoxy are each optionally substituted with one C₃-C₇ cycloalkylgroup;

R⁴ is selected from the group consisting of H, cyano, C₁-C₆ haloalkyl,and C₁-C₆ haloalkoxy; and

R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆alkylsulfonyl, C₃-C₇ cycloalkyl, halogen, and heteroaryl.

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Ij) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein:

m is 1 or 2;

R¹ is H or trifluoromethyl;

R² is selected from the group consisting of H, chloro, cyano, ethoxy,trifluoromethoxy, and trifluoromethyl;

R³ is selected from the group consisting of H, chloro, carboxamide,cyano, cyclohexyl, cyclohexylmethyl, cyclopentyloxy, cyclopentyl,cyclopropylmethoxy, 1,3-difluoropropan-2-yloxy, ethoxy, fluoromethoxy,isobutyl, isopropoxy, methoxy, and methylsulfonyl;

R⁴ is selected from the group consisting of H, cyano, trifluoromethoxy,and trifluoromethyl; and

R⁵ is selected from the group consisting of H, bromo, chloro,cyclobutyl, cyclopropyl, ethyl, fluoro, iodo, methyl, methylsulfonyl,and pyridin-2-yl.

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Ik) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein:

Y is N or CR¹;

Z is N or CR⁴;

R¹ is H;

R² is selected from the group consisting of cyano, C₁-C₆ haloalkoxy, andC₁-C₆ haloalkyl;

R³ is selected from the group consisting of H, C₁-C₆ alkoxy, C₁-C₆alkyl, and C₃-C₇ cycloalkyl;

R⁴ is H or cyano; and

R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, and halogen.

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Ik) and pharmaceutically acceptable salts,solvates, and hydrates thereof, wherein:

Y is N or CR¹;

Z is N or CR⁴;

R¹ is H;

R² is selected from the group consisting of cyano, trifluoromethoxy, andtrifluoromethyl;

R³ is selected from the group consisting of H, cyclohexyl, cyclopentyl,isobutyl, and isopropoxy;

R⁴ is H or cyano; and

R⁵ is selected from the group consisting of H, bromo, chloro,cyclobutyl, cyclopropyl, fluoro, iodo, and methyl.

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Im) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein:

R² is selected from the group consisting of cyano, C₁-C₆ haloalkoxy, andC₁-C₆ haloalkyl;

R³ is selected from the group consisting of H, C₁-C₆ alkoxy, C₁-C₆alkyl, and C₃-C₇ cycloalkyl; and

R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, and halogen.

Some embodiments of the present invention pertain to compounds selectedfrom compounds of Formula (Im) and pharmaceutically acceptable salts,solvates, and hydrates thereof, wherein:

R² is selected from the group consisting of cyano, trifluoromethoxy, andtrifluoromethyl;

R³ is selected from the group consisting of H, cyclohexyl, cyclopentyl,isobutyl, and isopropoxy; and

R⁵ is selected from the group consisting of H, bromo, chloro,cyclobutyl, cyclopropyl, fluoro, iodo, and methyl.

Esters and Prodrugs

One aspect of the present invention pertains to compounds of Formula(II) as synthetic intermediates useful in the preparation of compoundsof Formula (I) and/or prodrugs useful for the delivery of compounds ofFormula (I):

wherein:

m, n, R^(a), R², R³, Y, Z, and W have the same definitions as describedherein, supra and infra, and R⁶ is C₁-C₆ alkyl.

One aspect of the present invention pertains to compounds of Formula(IIa) as synthetic intermediates useful in the preparation of compoundsof Formula (Ia) and/or prodrugs useful for the delivery of compounds ofFormula (Ia):

wherein:

m, n, R², R³, Y, Z, and W have the same definitions as described herein,supra and infra, and R⁶ is C₁-C₆ alkyl.

It is appreciated that all of the embodiments described herein, supraand infra, that relate to the common variables shared between Compoundsof Formula (I) and (II) namely, m, n, R^(a), R², R³, Y, Z, and W, applyto Compounds of Formula (II) just as if they were each individuallydisclosed herewith specific reference to Formula (II).

One aspect of the present invention pertains to compounds of Formula(II).

One aspect of the present invention pertains to compounds of Formula(IIa).

In some embodiments, R⁶ is ethyl.

In some embodiments, R⁶ is tert-butyl.

It is appreciated that all of the embodiments described herein, supraand infra, that relate to the common variables shared between Compoundsof Formula (Ia) and (IIa) namely, n, R², R³, Y, Z, and W, apply toCompounds of Formula (IIa) just as if they were each individuallydisclosed herewith specific reference to Formula (IIa).

One aspect of the present invention pertains to compounds of Formula(II) as synthetic intermediates useful in the preparation of compoundsof Formula (I).

One aspect of the present invention pertains to compounds of Formula(IIa) as synthetic intermediates useful in the preparation of compoundsof Formula (Ia).

One aspect of the present invention pertains to compounds of Formula(II) as esters of compounds, described and shown herein, such ascompounds in Table A, where R⁶ is ethyl.

One aspect of the present invention pertains to compounds of Formula(IIa) as esters of compounds, described and shown herein, such ascompounds in Table A, where R⁶ is ethyl.

One aspect of the present invention pertains to compounds of Formula(II) as prodrugs useful for the delivery of compounds of Formula (I).

One aspect of the present invention pertains to compounds of Formula(IIa) as prodrugs useful for the delivery of compounds of Formula (Ia).

One aspect of the present invention pertains to compounds of Formula(II) useful as prodrugs of compounds of Formula (I).

One aspect of the present invention pertains to compounds of Formula(IIa) useful as prodrugs of compounds of Formula (Ia).

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group shown in TableA.

TABLE A Cmpd No. Chemical Structure Chemical Name 1

2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H- pyrrolo[1,2-a] indol-1-yl)acetic acid 2

2-(7-(3-cyano-5- (trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a] indol-1-yl)acetic acid 3

2-(9-chloro-7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 4

2-(7-(4-isobutyl-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 5

2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-9-fluoro-2,3-dihydro-1H- pyrrolo[1,2-a] indol-1-yl)acetic acid 6

2-(7-(3-cyano-4- isopropoxybenzyloxy)-2,3- dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 7

2-(9-bromo-7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 8

2-(9-chloro-7-(3-cyano-4- isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 9

2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H- pyrrolo [1,2-a]indol-1-yl)acetic acid 10

2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2- a] indol-1-yl)acetic acid 11

2-(9-cyclobutyl-7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2- a]indol-1-yl)acetic acid 12

2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 13

2-(7-(3-cyano-4- cyclohexylbenzyloxy)-2,3- dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 14

2-(6-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- a] imidazol-3-yl)acetic acid 15

2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H- pyrrolo[1,2-a]indol-1-yl)acetic acid 16

2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-9-(pyridin-2-yl)-2,3-dihydro-1H- pyrrolo[1,2-a]indol-1-yl)acetic acid 17

2-(7-(4-chloro-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 18

2-(7-(4-cyano-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 19

2-(7-(4-carbamoyl-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 20

2-(7-(4-(cyclopropylmethoxy)-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 21

2-(7-(4-(cyclohexylmethyl)-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 22

2-(7-(4- (methylsulfonyl)benzyloxy)-2,3- dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 23

2-(7-(2,4- bis(trifluoromethyl)benzyloxy)- 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 24

2-(7-(4-(1H-pyrazol-1- yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 25

2-(7-(4-(cyclopentyloxy)-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 26

2-(7-(3-cyano-4- isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2- a]indol-1-yl)acetic acid 27

2-(2-(3-cyano-5- (trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2- a]indol-9-yl)acetic acid 28

2-(7-(4-isopropoxy-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 29

2-(9-chloro-7-(4-isopropoxy-3- (trifluoromethyl)benzyloxy)-2,3-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 30

2-(9-chloro-7-(4- (cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3- dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 31

2-(7-(4-(fluoromethoxy)-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 32

2-(9-chloro-7-(4- (fluoromethoxy)-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 33

2-(7-(3-cyano-4- methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1- yl)acetic acid 34

2-(9-chloro-7-(3-cyano-4- methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1- yl)acetic acid 35

2-(7-(4-methoxy-3- (trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 36

2-(7-(4-isopropoxy-3- (trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H- pyrrolo[1,2-a]indol-1-yl)acetic acid 37

2-(7-(3-cyano-4- cyclopentylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol- 1-yl)acetic acid 38

2-(7-(3,4-diethoxybenzyloxy)- 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid 39

2-(7-(3-chloro-4-(1,3- difluoropropan-2- yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1- yl)acetic acid 40

2-(9-chloro-7-(3-chloro-4-(1,3- difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro- 1H-pyrrolo[1,2-a]indol-1- yl)acetic acid41

2-(7-(3-cyano-4- isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2- a]indol-1-yl)acetic acid 42

2-(9-chloro-7-(3-cyano-4- isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2- a]indol-1-yl)acetic acid 43

2-(7-(3-cyano-4- isopropoxybenzyloxy)-9- (methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1- yl)acetic acid 44

2-(2-(3-cyano-4- isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9- yl)acetic acid 45

2-(2-(4-isopropoxy-3- (trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2- a]indol-9-yl)acetic acid 46

2-(2-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2- a]indol-9-yl)acetic acid 47

2-(2-(3,4-diethoxybenzyloxy)- 6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid 48

2-(2-(3,5- bis(trifluoromethyl)benzyloxy)- 6,7,8,9-trahydropyrido[1,2-a]indol-9-yl)acetic acid

C(1) Ring Carbon Stereochemistry

Compounds of the present invention contain a fused tricyclic system.Present on one of the rings is either a —CH₂CO₂H group (n=1) or a—CH₂CH₂CO₂H group (n=2). The ring carbon to which the —CH₂CO₂H or the—CH₂CH₂CO₂H group is bonded, is referred to herein the C(1) ring carbon.It is understood that the stereochemistry for the C(1) ring carboncontained in the fused tricyclic ring system can be either R or S.

A. C(1) Ring Carbon “R” Stereochemistry

In some embodiments, the stereochemistry for the C(1) ring carbon is R.

Some embodiments of the present invention pertain to compounds ofFormula (IIb) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (IIb) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (IIc) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (IIc) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (IId) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (Hd) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (IIe) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (IIe) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid;(R)-2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-bromo-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-cyclobutyl-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid; and(R)-2-(6-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)aceticacid.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group:(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-carbamoyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-(cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-(methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(2,4-bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-(1H-pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-(cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-methoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-cyano-4-cyclopentylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3,4-diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(R)-2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(R)-2-(2-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(R)-2-(2-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(R)-2-(2-(3,4-diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(R)-2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid; and(R)-2-(2-(3-cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid.

B. C(1) Ring Carbon “S” Stereochemistry

In some embodiments, the stereochemistry for the C(1) ring carbon is S.

Some embodiments of the present invention pertain to compounds ofFormula (IIf) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (III) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (IIg) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (IIg) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (IIh) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (IIh) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to compounds ofFormula (IIi) and pharmaceutically acceptable salts, solvates, andhydrates thereof:

wherein each variable in Formula (IIi) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group:(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-bromo-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-cyclobutyl-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid, and(S)-2-(6-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)aceticacid.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following group:(S)-2-(2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-carbamoyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-(cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-(methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(2,4-bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-(1H-pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-(cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-methoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-4-cyclopentylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3,4-diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;(S)-2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(S)-2-(2-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(S)-2-(2-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(S)-2-(2-(3,4-diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;(S)-2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid; and(S)-2-(2-(3-cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid.

Additionally, individual compounds and chemical genera of the presentinvention, for example, those compounds found in Table A includingdiastereomers and enantiomers thereof, encompass all pharmaceuticallyacceptable salts, solvates, and hydrates, thereof.

It is understood that the present invention embraces each diastereomer,each enantiomer and mixtures thereof of each compound and genericformulae disclosed herein just as if they were each individuallydisclosed with the specific stereochemical designation for each chiralcarbon. Separation of the individual isomers (such as, by chiral HPLC,recrystallization of diastereomeric mixtures, and the like) or selectivesynthesis (such as, by enantiomeric selective syntheses and the like) ofthe individual isomers is accomplished by application of various methodswhich are well known to practitioners in the art.

The compounds of the Formula (Ia) of the present invention may beprepared according to relevant published literature procedures that areused by one skilled in the art. Exemplary reagents and procedures forthese reactions appear hereinafter in the working examples.

Protection and deprotection may be carried out by procedures generallyknown in the art (see, for example, Greene, T. W. and Wuts, P. G. M.,Protecting Groups in Organic Synthesis, 3^(rd) Edition, 1999 [Wiley];incorporated herein by reference in its entirety).

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et al.)

While it is possible that, for use in the prophylaxis or treatment, acompound of the invention may, in an alternative use, be administered asa raw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt, solvate, hydrate or derivative thereof together with one or morepharmaceutically acceptable carriers thereof and/or prophylacticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and not overlydeleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use; in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules orsuspensions, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a salt, solvate, hydrate orphysiologically functional derivative thereof can be used as activeingredients in pharmaceutical compositions, specifically as S1P1receptor modulators. The term “active ingredient” is defined in thecontext of a “pharmaceutical composition” and is intended to mean acomponent of a pharmaceutical composition that provides the primarypharmacological effect, as opposed to an “inactive ingredient” whichwould generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits and as is customary and known to the physician, it isto be tailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but are not limited to, about 0.001 mgto about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg toabout 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg toabout 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4 doses. Depending on the individual and as deemedappropriate by the patient's physician or caregiver it may be necessaryto deviate upward or downward from the doses described herein.

The amount of active ingredient or an active salt, solvate or hydratederivative thereof, required for use in treatment will vary not onlywith the particular salt selected but also with the route ofadministration, the nature of the condition being treated and the ageand condition of the patient and will ultimately be at the discretion ofthe attendant physician or clinician. In general, one skilled in the artunderstands how to extrapolate in vivo data obtained in one modelsystem, typically an animal model, to another, such as a human. In somecircumstances, these extrapolations may merely be based on the weight ofthe animal model in comparison to another, such as a mammal, preferablya human, however, more often, these extrapolations are not simply basedon weights, but rather incorporate a variety of factors. Representativefactors include the type, age, weight, sex, diet and medical conditionof the patient, the severity of the disease, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized, whetheran acute or chronic disease state is being treated or prophylaxis isconducted or whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors including those cited above. Thus, theactual dosage regimen employed may vary widely and therefore may deviatefrom a preferred dosage regimen and one skilled in the art willrecognize that dosage and dosage regimens outside these typical rangescan be tested and, where appropriate, may be used in the methods of thisinvention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, as 2,3, 4 or more sub-doses per day. The sub-dose itself may be furtherdivided, e.g., into a number of discrete loosely spaced administrations.The daily dose can be divided, especially when relatively large amountsare administered as deemed appropriate, into several, for example 2, 3or 4 part administrations. If appropriate, depending on individualbehavior, it may be necessary to deviate upward or downward from thedaily dose indicated.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the suitable pharmaceutically acceptable carrier canbe either solid, liquid or a mixture of both. Solid form preparationsinclude powders, tablets, pills, capsules, cachets, suppositories anddispersible granules. A solid carrier can be one or more substanceswhich may also act as diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tabletdisintegrating agents, or encapsulating materials.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesired shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet may befrom 0.5 to about 90 percent of the active compound. However, an artisanwould know when amounts outside of this range are necessary. Suitablecarriers for powders and tablets include magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein (e.g., by stirring). Themolten homogenous mixture is then poured into convenient sized molds,allowed to cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising the active agent in a flavored base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols (e.g., nasal aerosols, by inhalation), this canbe carried out, for example, using a spray, a nebulizer, a pumpnebulizer, an inhalation apparatus, a metered inhaler or a dry powderinhaler. Pharmaceutical forms for administration of the compounds of thepresent invention as an aerosol can be prepared by processes well knownto the person skilled in the art. Solutions or dispersions of thecompounds of the present invention or a pharmaceutically acceptablesalt, solvate, hydrate or derivative thereof in water, water/alcoholmixtures or suitable saline solutions, for example, can be employedusing customary additives (e.g., benzyl alcohol or other suitablepreservatives), absorption enhancers for increasing the bioavailability,solubilizers, dispersants and others and, if appropriate, customarypropellants (e.g., carbon dioxide, CFCs, such as,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane and the like). The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder (e.g., a powder mix of the compound in a suitable powder basesuch as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP)). Conveniently the powdercarrier will form a gel in the nasal cavity. The powder composition maybe presented in unit dose form (e.g., capsules, cartridges) as forgelatin or blister packs from which the powder may be administered bymeans of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

In some embodiments, the compositions are tablets or capsules for oraladministration.

In some embodiments, the compositions are liquids for intravenousadministration.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed by Berge et al., Journal ofPharmaceutical Sciences, 66:1-19 (1977), incorporated herein byreference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds of the present invention can be converted to “pro-drugs.” Theterm “pro-drugs” refers to compounds that have been modified withspecific chemical groups known in the art and that when administeredinto an individual undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when S1P1 receptor agonists are utilized as activeingredients in a pharmaceutical composition, these are not intended foruse only in humans, but in other non-human mammals as well. Indeed,recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as S1P1receptor agonists, for the treatment of an S1P1 receptor-associateddisease or disorder in companionship animals (e.g., cats, dogs, etc.)and in livestock animals (e.g., cows, chickens, fish, etc.). Those ofordinary skill in the art are readily credited with understanding theutility of such compounds in such settings.

Hydrates and Solvates

It is understood that when the phrase “pharmaceutically acceptablesalts, solvates and hydrates” is used when referring to a particularformula herein, it is intended to embrace solvates and/or hydrates ofcompounds of the particular formula, pharmaceutically acceptable saltsof compounds of the particular formula as well as solvates and/orhydrates of pharmaceutically acceptable salts of compounds of theparticular formula.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be apparent tothose skilled in the art that the following dosage forms may comprise,as the active component, either a compound of the invention or apharmaceutically acceptable salt or as a solvate or hydrate thereof.Moreover, various hydrates and solvates of the compounds of theinvention and their salts will find use as intermediates in themanufacture of pharmaceutical compositions. Typical procedures formaking and identifying suitable hydrates and solvates, outside thosementioned herein, are well known to those in the art; see for example,pages 202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates,Solvates, and Amorphous Solids,” in: Polymorphism in PharmaceuticalSolids, ed. Harry G. Britton, Vol. 95, Marcel Dekker, Inc., New York,1999, incorporated herein by reference in its entirety. Accordingly, oneaspect of the present invention pertains to hydrates and solvates ofcompounds of Formula (I) and (Ia), or Formula (II) and (IIa) and/ortheir pharmaceutical acceptable salts, as described herein, that can beisolated and characterized by methods known in the art, such as,thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infraredspectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration,high resolution X-ray diffraction, and the like. There are severalcommercial entities that provide quick and efficient services foridentifying solvates and hydrates on a routine basis. Example companiesoffering these services include Wilmington PharmaTech (Wilmington,Del.), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, Conn.).

Other Utilities

Another object of the present invention relates to radiolabeledcompounds of the present invention that are useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the S1P1 receptor in tissue samples,including human and for identifying S1P1 receptor ligands by inhibitionbinding of a radiolabeled compound. It is a further object of thisinvention to develop novel S1P1 receptor assays which comprise suchradiolabeled compounds.

The present invention embraces isotopically-labeled compounds of thepresent invention. Isotopically or radiolabeled compounds are thosewhich are identical to compounds disclosed herein, but for the fact thatone or more atoms are replaced or substituted by an atom having anatomic mass or mass number different from the atomic mass or mass numbermost commonly found in nature. Suitable radionuclides that may beincorporated in compounds of the present invention include, but are notlimited, to ²H (also written as D for deuterium), ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radiolabeled compounds will depend on thespecific application of that radiolabeled compound. For example, for invitro S1P1 receptor labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S will generally be mostuseful. For radio-imaging applications ¹¹C, ¹¹F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radiolabeled” or “labeled compound” is acompound as described herein, for example, a compound found in Formula(I), (Ia), (Ic), (Ie), (Ig), (Ij), (Ik), (Im), (IIa), (IIb), (IIc),(IId), (IIe), (IIf), (IIg), (IIh), or (IIi), or compound of Table A,containing at least one radionuclide. In some embodiments theradionuclide is selected from the group consisting of ³H, ¹⁴C, ¹²⁵I,³⁵S, and ⁸²Br.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in FIGS. 1 to 10 and examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or a scarcer radio-isotope or nonradioactiveisotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. Certain synthetic methods, for example, forincorporating activity levels of tritium into target molecules, are asfollows:

A. Catalytic Reduction with Tritium Gas: This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]: This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with Lithium Aluminum Hydride [³H]: This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling: This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]: This procedure is usuallyemployed to prepare O-methyl or N-methyl [³H] products by treatingappropriate precursors with high specific activity methyl iodide [³H].This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions: This procedure transforms an aryl amineor a heteroaryl amine into a diazonium salt, such as a diazoniumtetrafluoroborate salt and subsequently to ¹²⁵I labeled compound usingNa¹²⁵I. A represented procedure was reported by Zhu, G-D. and co-workersin J. Org. Chem., 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols: This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999,42, S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I: This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresentative procedure was reported by Le Bas, M.-D. and co-workers inJ. Labelled Compd. Radiopharm. 2001, 44, S280-S282.

A radiolabeled S1P1 receptor compound of Formula (I) or (Ia), or Formula(IIa) or (IIa) can be used in a screening assay to identify/evaluatecompounds. In general terms, a newly synthesized or identified compound(i.e., test compound) can be evaluated for its ability to reduce bindingof the “radiolabeled compound of Formula (I) or (Ia), or Formula (IIa)or (IIa)” to the S1P1 receptor. Accordingly, the ability of a testcompound to compete with the “radiolabeled compound of Formula (I) or(Ia), or Formula (IIa) or (IIa)” for the binding to the S1P1 receptordirectly correlates to its binding affinity.

The labeled compounds of the present invention bind to the S1P1receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those of skill in the art based upon, inter alia, a review of thisdisclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1 Syntheses of Compounds of the Present Invention

Illustrated syntheses for compounds of the present invention are shownin FIGS. 1 through 10 where the variables have the same definitions asused throughout this disclosure.

The compounds of the invention and their syntheses are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to the AutoNom version 2.2,CS ChemDraw Ultra Version 9.0.7. In certain instances common names areused and it is understood that these common names would be recognized bythose skilled in the art.

Chemistry:

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on aBruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI(Broad Band Inverse) and z-gradient. Proton nuclear magnetic resonance(¹H NMR) spectra were also recorded on a Bruker Avance-500 equipped aBBI (Broad Band Inverse) and z-gradient. Chemical shifts are given inparts per million (ppm) with the residual solvent signal used asreference. NMR abbreviations are used as follows: s=singlet, d=doublet,dd=doublet of doublets, t=triplet, q=quartet, m=multiplet, bs=broadsinglet. Microwave irradiations were carried out using a SmithSynthesizer™ or an Emrys Optimizer™ (Biotage). Thin-layer chromatography(TLC) was performed on silica gel 60 F₂₅₄ (Merck), preparatorythin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60A 1 mm plates (Whatman) and column chromatography was carried out on asilica gel column using Kieselgel 60, 0.063-0.200 mm (Merck).Evaporation was done under reduced pressure on a BUN rotary evaporator.Celite® 545 was used for filtration of palladium.

LCMS spec: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.Resolution of Compound 6 by supercritical fluid chiral separation(Example 1.2): Chiral Technologies, Inc (USA).

Example 1.1 Preparation of2-(7-(3-Cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 2) Step A: Preparation of7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one

To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (30 g, 112 mmol)in toluene (500 mL) was added portionwise sodium hydride (60% dispersionin mineral oil, 9.40 g, 235 mmol). Vigorous gas evolution was observed.The resulting white suspension was heated to 110° C. Butyl acrylate(35.1 mL, 246 mmol) was added dropwise (using a syring pump) over 24 hwhile stirring vigorously at an internal temperature of 110° C.Additional butyl acrylate (10 mL) was added in one portion and stirringwas continued at 110° C. for 4 h followed by additional sodium hydride(60% dispersion in mineral oil, 5 g) and butyl acrylate (10 mL). 4 hlater, butyl acrylate (6 mL) was added. Stirring was continued at 110°C. for a total of 48 h. The reaction was cooled in an ice-bath and 2 MHCl (400 mL) was added carefully. The layers were separated and theaqueous layer was extracted with dichloromethane (2×200 mL). Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated. The resulting orange residue was dissolved inacetic acid (900 mL) and water (100 mL). The orange solution wasrefluxed 16 h before the solvents were removed under vacuum. To theresidue was added dichloromethane (300 mL). The resulting precipitatewas collected by filtration and rinsed twice with dichloromethane toprovide the title compound. LCMS m/z=250.2 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.20 (t, J=6.1 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 6.92 (s,1H), 7.46 (dd, J=8.8, 1.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.98 (d,J=2.0 Hz, 1H).

Step B: Preparation of tert-Butyl2-(7-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate

To a solution of 7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (0.50g, 1.999 mmol) in THF (10 mL) was added(tert-butoxycarbonylmethylene)triphenylphosphorane (1.881 g, 5.00 mmol).The mixture was stirred at 65° C. for 16 h and concentrated. The residuewas purified by silica gel flash chromatography to provide the titlecompound (0.50 g). LCMS m/z 348 [M+H]⁺.

Step C: Preparation of tert-Butyl2-(7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate

To a solution of tert-butyl2-(7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (300 mg,0.86 mmol) and potassium acetate (296 mg, 3.02 mmol) in dioxane (10 mL)was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(241 mg, 0.95 mmol). Nitrogen was bubbled through the mixture for 10min. PdCl₂(dppf) (31.5 mg, 0.04 mmol) was added and the mixture wasstirred under nitrogen at 90° C. for 1.5 h. The mixture wasconcentrated. The residue was purified by silica gel flashchromatography to provide the title compound as a yellow solid (340 mg).LCMS m/z=396.3 [M+H]⁺.

Step D: Preparation of tert-Butyl2-(7-Hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate

To a solution of tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate(330 mg, 0.835 mmol) in THF (10 mL) was added a 2.0 M aqueous solutionof sodium hydroxide (4.17 mL, 8.35 mmol). Then was added dropwisehydrogen peroxide (30 wt % aqueous solution, 0.853 mL, 8.35 mmol). Themixture was stirred at 23° C. for 25 min before 0.5 M HCl (50 mL) wasadded. The resulting mixture was extracted with dichloromethane (2×35mL). The combined organic extracts were dried over MgSO₄, filtered andconcentrated under vacuum. The residue was purified by silica gel flashchromatography to provide the title compound as a pale yellow solid (186mg). LCMS m/z=286.3 [M+H]⁺.

Step E: Preparation of tert-Butyl2-(7-Hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (230mg, 0.806 mmol) was dissolved in ethyl acetate (5 mL). Degussa wet (50wt % water) 10% Pd/C (223 mg, 0.105 mmol) was added and the mixture wasstirred in a hydrogenation reactor under 95 psi hydrogen for 3 h. Themixture was filtered through Celite®. The filtrate was concentrated andpurified by silica gel flash chromatography to provide the titlecompound as a white solid (131 mg). LCMS m/z=288.3 [M+H]⁺.

Step F: Preparation of tert-Butyl2-(7-(3-Cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To an ice-cooled solution of tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (131 mg,0.456 mmol), 3-(hydroxymethyl)-5-(trifluoromethoxy)benzonitrile (114 mg,0.524 mmol) and triphenylphosphine (179 mg, 0.684 mmol) in THF (3 mL)was added diisopropyl diazene-1,2-dicarboxylate (0.135 mL, 0.684 mmol)dropwise. After stirring at 0° C. for 15 min, the cooling bath wasremoved and the mixture was stirred at 23° C. for 3 h and thenconcentrated. The residue was purified by preparative TLC to provide thetitle compound as a yellow solid (50 mg). LCMS m/z=487.4 [M+H]⁺.

Step G: Preparation of2-(7-(3-Cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To a solution of tert-butyl2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(50 mg, 0.103 mmol) and thioanisole (0.121 mL, 1.028 mmol) indichloromethane (1 mL) was added trifluoroacetic acid (0.305 mL, 4.11mmol). The solution was stirred at 23° C. for 3 h. The reaction mixturewas concentrated. The residue was triturated with hexanes and purifiedby HPLC to provide the title compound as a white solid (19 mg). LCMSm/z=431.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.27-2.36 (m, 1H), 2.68(dd, J=16.6, 8.2 Hz, 1H), 2.87-2.96 (m, 2H), 3.76 (quintet, J=7.5 Hz,1H), 3.99-4.05 (m, 1H), 4.11-4.17 (m, 1H), 5.11 (s, 2H), 6.13 (s, 1H),6.86 (dd, J=8.7, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz,1H), 7.43 (s, 1H), 7.57 (s, 1H), 7.68 (s, 1H).

Example 1.2 Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 6) Step A: Preparation of7-(Benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one

Ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (25 g, 85 mmol) wasdissolved in toluene (125 mL) and 60% sodium hydride in mineral oil(7.79 g, 195 mmol) was added portionwise. The reaction was stirred for50 min and butyl acrylate (26.6 mL, 186 mmol) was added. The reactionwas stirred at room temperature for 1.5 h and additional butyl acrylate(20 mL) was added. After stirring for 30 min, the solution was warmed to70° C. and stirred for 1 h. The reaction was cooled to room temperatureand sodium hydride (4.0 g) was added. The reaction was warmed to 70° C.causing the reaction to reflux. The heat source was removed and butylacrylate (15 mL) was added and heating at 70° C. was resumed. After 30min, the heat source was removed and the reaction was left to stir for16 h. Water (25 mL) was added followed by 1.0 M HCL (250 mL) and 12 MHCL (50 mL). The aqueous layer was removed and the toluene was washedtwo times with water (100 mL). The toluene layer was concentrated underreduced pressure and the concentrate was taken up in acetic acid (120mL) and water (12 mL). The reaction mixture was heated under reflux andstirred for 24 h. The reaction mixture was cooled to room temperatureand water (200 mL) was added. The aqueous mixture was diluted with ethylacetate and washed with water and brine. The ethyl acetate layer wasfiltered through a pad of Celite® and the filtrate was concentratedunder reduced pressure. The residue was purified by crystallization frommethanol to provide the title compound (8.0 g). LCMS m/z=278.2 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20 (t, J=6.6 Hz, 2H), 4.41 (t, J=6.2Hz, 2H), 5.11 (s, 2H), 6.91 (s, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 7.19(d, J=2.4 Hz, 1H), 7.30-7.42 (m, 4H), 7.44-7.49 (m, 2H).

Step B: Preparation of tert-Butyl2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate

7-(Benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (3.6 g, 12.98mmol) and (tert-butoxycarbonylmethylene)triphenylphosphorane (5.86 g,15.58 mmol) were dissolved in toluene (40 mL) and the reaction mixturewas heated under reflux and stirred for 24 h. The solution was cooled toroom temperature. The precipitate was collected by filtration. Thefiltrate was concentrated under reduced pressure to yield additionalwhite solid. The process was repeated to provide the title compound(1.391 g). LCMS m/z=376.4 [M+H]⁺.

Step C: Preparation of tert-Butyl2-(7-Hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl-2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate(1.391 g, 3.70 mmol) was dissolved in THF (25 mL) and 10% palladium oncarbon (50% in water, 217 mg) was added. The reaction mixture was placedunder 225 psi of hydrogen in a hydrogenation reactor for 24 h. Themixture was filtered and the filtrate was concentrated under reducedpressure to provide tert-butyl2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. Theabove material was taken up in a mixture of THF (20 mL) and EtOH (20 mL)and Pd(OH)₂/C (250 mg) was added. The reaction mixture was placed under200 psi of hydrogen in a hydrogenation reactor for 2 days. AdditionalPd(OH)₂/C (250 mg) was added and the reaction mixture was placed under300 psi of hydrogen in a hydrogenation reactor for 24 h. Pd(OH)₂/C (250mg) was again added and the vessel placed under 500 psi of hydrogen in ahydrogenation reactor for 24 h. The hydrogenation reactor was warmed to50° C. for 8 h. The reaction mixture was cooled to room temperature andAcOH (5 mL) was added. The reaction mixture was placed under 500 psi ofhydrogen for 16 h. The reaction mixture was filtered through Celite® andthe filtrate was concentrated under reduced pressure to provide amixture of the title compound and tert-butyl2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate.The title compound (150 mg) was isolated by silica gel columnchromatography. tert-Butyl2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(600 mg) was dissolved in toluene (100 mL) and Pd/C (1.0 g) was added.The reaction mixture was warmed to 80° C. and stirred for 2 days. Thereaction mixture was filtered through Celite® and the title compound(250 mg) was isolated as a white solid resulting from precipitationduring concentration of the filtrate. LCMS m/z=288.3 [M+H]⁺.

Step D: Preparation of tert-Butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(461 mg, 1.60 mmol) was dissolved in DMF (3.0 mL) and5-(chloromethyl)-2-isopropoxybenzonitrile (337 mg, 1.60 mmol) and cesiumcarbonate (533 mg, 1.60 mmol) were added. The reaction mixture wasstirred at room temperature for 2 days and partitioned between ethylacetate and water. The organics were removed and the aqueous mixture wasextracted two times with ethyl acetate. The combined extracts were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidual oil was dissolved in methanol (10 mL) and cooled to 0° C. Theprecipitate was collected by filtration and triturated with 10% ethylacetate/hexanes to provide the title compound (462 mg). LCMS m/z=461.5[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (d, J=6.1 Hz, 6H), 1.44 (s,9H), 2.15-2.25 (m, 1H), 2.51-2.68 (m, 2H), 2.71-2.81 (m, 1H), 3.53-3.61(m, 1H), 3.91-3.99 (m, 1H), 4.04-4.13 (m, 1H), 4.78 (septet, J=6.1 Hz,1H), 5.02 (s, 2H), 5.99 (s, 1H), 6.74 (dd, J=8.7, 2.4 Hz, 1H), 7.06 (d,J=2.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.70 (dd,J=8.7, 2.3 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H).

Step E: Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

tert-Butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(452 mg, 0.981 mmol) was added to a solution of2-amino-3-mercaptopropanoic acid (214 mg, 1.767 mmol) in TFA (5 mL) andwas stirred at room temperature for 15 min. The reaction mixture waspoured into ice water. The white precipitate was collected by filtrationto provide the title compound (342 mg). LCMS m/z=405.5 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.40 (d, J=6.1 Hz, 6H), 2.26-2.36 (m, 1H), 2.66(dd, J=16.4, 8.5 Hz, 1H), 2.85-2.97 (m, 2H), 3.72-3.80 (m, 1H),3.98-4.06 (m, 1H), 4.10-4.17 (m, 1H), 4.65 (septet, J=6.1 Hz, 1H), 5.00(s, 2H), 6.12 (s, 1H), 6.84 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz,1H), 7.06 (d, J=2.4 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.8,2.4 Hz, 1H), 7.64 (d, J=2.1 Hz, 1H).

Resolution of Compound 6 by Chiral HPLC.

Column: normal phase preparative ChiralPak AD-H column, 5×25 cm ID

Eluent: 65% CO₂/35% IPA

Pressure: 270 bars (inlet) and 100 bars (back)

Gradient: Isocratic

Flow: 400 mL/min

Temperature: 25° C. Detector: 230 nm

Retention Times: 1^(st) enantiomer: 6.7 min; 2^(nd) enantiomer: 9.2 min.

Example 1.3 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 12) Step A: Preparation of tert-Butyl2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.563 g, 1.960 mmol),4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (0.515 g,1.960 mmol) and cesium carbonate (0.703 g, 2.156 mmol) in DMF (4 mL)were heated to 50° C. for 16 h in a 20 mL sealed scintillation vial. Thereaction mixture was filtered by vacuum filtration through Celite® andwashed with EtOAc (3×10 mL). The filtrate was concentrated under reducedpressure. The residue was taken up in EtOAc (25 mL), washed with water(2×25 mL), saturated NaCl (20 mL), dried over MgSO₄ and filtered. Thefiltrate was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography to give a yellow stickyoil. A precipitate, formed by addition of hexanes to the oil, wascollected by filtration, was washed with hexanes (3×20 mL) and dried(vacuum oven) to provide the title compound as a white solid (0.6273 g).LCMS m/z=514.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44 (s, 9H),1.57-1.72 (m, 4H), 1.81-1.87 (m, 2H), 1.95-2.04 (m, 2H), 2.15-2.24 (m,1H), 2.53-2.67 (m, 2H), 2.71-2.81 (m, 1H), 3.20-3.27 (m, 1H), 3.57(quintet, J=7.75 Hz, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 5.13 (s,2H), 5.99 (s, 1H), 6.77 (dd, J=8.65, 2.08 Hz, 1H), 7.07 (d, J=2.27 Hz,1H), 7.19 (d, J=8.72 Hz, 1H), 7.62 (d, J=8.72 Hz, 1H) 7.68-7.70 (m, 2H).

Step B: Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

tert-Butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.800 g, 1.558 mmol) was added to a solution of2-amino-3-mercaptopropanoic acid (0.189 g, 1.558 mmol) in TFA (10 mL).The reaction mixture was stirred at 23° C. for 15 min in a 20 mL sealedscintillation vial. After 15 min the reaction mixture was poured intoice water and a precipitate formed. The precipitate was collected byfiltration, washed with hexanes (3×20 mL) and dried (vacuum oven) toprovide the title compound as a white solid (0.595 g). LCMS m/z=458.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53-1.74 (m, 4H), 1.79-1.89 (m,2H), 1.94-2.04 (m, 2H), 2.15-2.26 (m, 1H), 2.51-2.69 (m, 2H), 2.72-2.83(m, 1H), 3.23-3.27 (m, 1H), 3.58 (quintet, J=7.20 Hz, 1H), 3.91-4.00 (m,1H), 4.05-4.14 (m, 1H), 5.13 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.72,2.40 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.62 (d,J=8.08 Hz, 1H), 7.68-7.71 (m, 2H), 12.27 (s, 1H).

Resolution of Compound 12 by Chiral HPLC.

Column: normal phase preparative ChiralPak AD-H column, 20×250 mm ID, 5μm particle size

Eluent: Acetonitrile 100% Gradient: Isocratic

Flow: 7 mL/min

Detector: 280 nm

Retention Times: 1^(st) enantiomer: 15 min; 2^(nd) enantiomer: 18 min.

Example 1.4 Preparation of2-(9-Chloro-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 3)

To a solution of2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid (34 mg, 0.074 mmol) dissolved in DCM (0.500 mL) and cooled to 0° C.was added NCS (9.92 mg, 0.074 mmol). The reaction was stirred at 0° C.for 15 min in a 20 mL sealed scintillation vial. After 15 min, thereaction mixture was diluted with DCM and washed with water (2×10 mL),washed with sodium thiolsulfate pentahydrate (aq.) (2×10 mL), dried overMgSO₄ and filtered. The filtrate was concentrated under reduced pressureto give the title compound as a light yellow solid (32 mg). LCMSm/z=492.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.73 (m, 4H),1.80-1.89 (m, 2H), 1.95-2.05 (m, 2H), 2.24-2.35 (m, 1H), 2.52-2.58 (m,1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.36, 4.11 Hz, 1H), 3.21-3.29 (m,1H), 3.64-3.72 (m, 1H), 3.95-4.05 (m, 1H), 4.11-4.19 (m, 1H), 5.18 (s,2H), 6.87 (dd, J=8.78, 2.46 Hz, 1H), 6.98 (d, J=2.27 Hz, 1H), 7.29 (d,J=8.84 Hz, 1H), 7.63 (d, J=7.96 Hz 1H), 7.69-7.76 (m, 2H), 12.35 (bs,1H).

Example 1.5 Preparation of2-(9-Bromo-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrroloindol-1-yl)acetic Acid (Compound 7)

From2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid and NBS, in a similar manner to the one described in Example 1.4,the title compound was obtained as a light yellow solid. LCMS m/z=536.6[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55-1.71 (m, 4H), 1.80-1.89 (m,2H), 1.95-2.04 (m, 2H), 2.25-2.36 (m, 1H), 2.51-2.57 (m, 1H), 2.78-2.88(m, 1H), 2.98 (dd, J=16.42, 3.66 Hz, 1H), 3.22-3.28 (m, 1H), 3.58-3.67(m, 1H), 3.98-4.06 (m, 1H), 4.13-4.20 (m, 1H), 5.18 (s, 2H), 6.88 (dd,J=8.84, 2.40 Hz, 1H), 6.91 (d, J=2.15 Hz, 1H), 7.29 (d, J=8.72 Hz, 1H),7.63 (d, J=8.21 Hz, 1H), 7.70-7.76 (m, 2H), 12.33 (bs, 1H).

Example 1.6 Preparation of2-(6-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)aceticAcid (Compound 14) Step A: Preparation of Ethyl2-(2-oxopyrrolidin-3-yl)Acetate

tert-Butyl 2-oxopyrrolidine-1-carboxylate (10 g, 54.0 mmol) wasdissolved in THF (75 mL) and cooled to −78° C. LDA (1.8 M inTHF/heptane, 30.0 mL, 54.0 mmol) was added and the solution was stirredfor 1 h. Ethyl 2-bromoacetate (9.02 g, 54.0 mmol) was added and themixture was stirred for 1 h and allowed to warm to room temperature andstirred for 16 h. The reaction mixture was partitioned between water andEtOAc. The aqueous layer was extracted two times with EtOAc and thecombined extracts were dried (sodium sulfate), filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography to provide partially purified tert-butyl3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate. tert-Butyl3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate (4.72 g, 17.40mmol) was dissolved in EtOH (30 mL) and TFA (10 mL). The reaction wasstirred at room temperature for 2 h and 20 mL of TFA was added. Afterstirring for an additional 2 h, the reaction mixture was concentratedunder reduced pressure and purified by column chromatography to providethe title compound (1.77 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.26 (t,J=7.2 Hz, 3H), 1.81-1.93 (m, 1H), 2.35-2.49 (m, 2H), 2.75-2.85 (m, 1H),2.88 (dd, J=16.4, 3.9 Hz, 1H), 3.31-3.40 (m, 2H), 4.09-4.21 (m, 2H),5.96 (bs, 1H).

Step B: Preparation of Ethyl2-(1-(4-(Benzyloxy)-2-nitrophenyl)-2-oxopyrrolidin-3-yl)acetate

Ethyl 2-(2-oxopyn-olidin-3-yl)acetate (1.77 g, 10.34 mmol) was dissolvedin DMF (20 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil,0.414 g, 10.34 mmol) was added.

After stirring for several min, the reaction was allowed to warm to roomtemperature and stirred for 10 min.4-(Benzyloxy)-1-fluoro-2-nitrobenzene (2.56 g, 10.34 mmol) was added andthe mixture was stirred at room temperature for 21 h. The reaction waspoured into water and acidified to pH 5 with 1.0 M HCL. The aqueousmixture was extracted three times with EtOAc and the combined extractswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by column chromatography to providethe title compound (1.09 g). LCMS m/z=399.4 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.27 (t, J=7.2 Hz, 3H), 1.97-2.01 (m, 1H), 2.46-2.59 (m,2H), 2.95 (dd, J=12.9, 3.8 Hz, 1H), 2.96-106 (m, 1H), 3.69-3.76 (m, 1H),3.79-3.88 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 5.13 (s, 2H), 6.90 (d, J=2.5Hz, 1H), 6.94 (dd, J=9.0, 2.7 Hz, 1H), 7.37-7.42 (m, 5H), 8.04 (d, J=9.1Hz, 1H).

Step C: Preparation of Ethyl2-(1-(2-Amino-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl)acetate

Ethyl 2-(1-(4-(benzyloxy)-2-nitrophenyl)-2-oxopyrrolidin-3-yl)acetate(1.09 g, 2.73 mmol) was taken up in EtOH and THF (1:1 mixture, 40 mL)and Pd/C (500 mg) was added. The reaction was pressurized with hydrogen(500 psi) in a bomb reactor and stirred at room temperature for 1 h. Thereaction mixture was filtered through a pad of Celite® and the filtratewas concentrated under reduced pressure to provide the title compound(752 mg). LCMS m/z=279.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.27 (t,J=7.1 Hz, 3H), 1.96-2.08 (m, 1H), 2.38-2.48 (m, 1H), 2.70 (dd, J=16.9,7.7 Hz, 1H), 2.86 (dd, J=17.0, 4.0 Hz, 1H), 2.95-3.05 (m, 1H), 3.63-3.79(m, 2H), 4.18 (q, J=7.2 Hz, 2H), 6.53 (d, J=2.7 Hz, 1H), 6.59 (dd,J=8.6, 2.6 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H).

Step D: Preparation of Ethyl2-(6-Hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate

Ethyl 2-(1-(2-amino-4-hydroxyphenyl)-2-oxopyrrolidin-3-yl)acetate (0.740g, 2.66 mmol) was dissolved in AcOH (50 mL) and was warmed to 75° C. andstirred for 8 h. The reaction mixture was concentrated under reducedpressure and the residue was taken up in toluene and concentrated again.The black concentrate was filtered through a plug of silica eluting with10% MeOH in DCM. The filtrate was concentrated to provide the titlecompound (666 mg). LCMS m/z=261.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm1.19 (t, J=7.1 Hz, 3H), 2.25-2.36 (m, 1H), 2.63 (dd, J=16.4, 8.8 Hz,1H), 2.79-2.89 (m, 2H), 3.48-3.56 (m, 1H), 3.90-3.98 (m, 1H), 4.02-4.14(m, 2H), 6.61 (dd, J=8.6, 2.3 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 7.30 (d,J=8.6 Hz, 1H), 9.11 (bs, 1H).

Step E: Preparation of Ethyl2-(6-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate

Ethyl2-(6-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate(0.1 g, 0.384 mmol) was dissolved in DMF (1.0 mL) and cesium carbonate(0.150 g, 0.461 mmol) and4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (0.111 g,0.423 mmol) were added. The reaction mixture was stirred at roomtemperature for 1.5 h and then warmed to 40° C. After stirring for 1 h,the reaction mixture was diluted with water and extracted three timeswith EtOAc. The combined extracts were dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography to provide the title compound (126mg). LCMS m/z=487.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) 5 ppm 1.26 (t, J=7.2Hz, 3H), 1.55-1.65 (m, 2H), 1.67-1.78 (m, 2H), 1.81-1.91 (m, 2H),2.04-2.14 (m, 2H), 2.36-2.47 (m, 1H), 2.62 (dd, J=16.4, 9.7 Hz, 1H),2.97-3.07 (m, 1H), 3.16 (dd, J=16.8, 3.8 Hz, 1H), 3.33-3.43 (m, 1H),3.64-3.74 (m, 1H), 3.97-4.05 (m, 1H), 4.09-4.21 (m, 3H), 5.09 (s, 2H),6.87 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 7.49 (d, J=8.3 Hz,1H), 7.56-7.61 (m, 2H), 7.68 (s, 1H).

Step F: Preparation of2-(6-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)aceticAcid

Ethyl2-(6-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate(0.109 g, 0.224 mmol) was dissolved in dioxane (2.5 mL) and 1.0 Maqueous lithium hydroxide (0.672 mL, 0.672 mmol) was added. The reactionmixture was stirred at room temperature for 1.5 h and then acidified (pH2) with 1.0 M HCl. The reaction mixture was extracted three times withEtOAc and the combined extracts were dried over sodium sulfate, filteredand concentrated under reduced pressure to provide the title compound(103 mg). LCMS m/z=459.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.54-1.65 (m, 2H), 1.67-1.79 (m, 2H), 1.80-1.91 (m, 2H), 2.05-2.14 (m,2H), 2.42-2.53 (m, 1H), 2.89 (d, J=7.1 Hz, 1H), 2.95-3.22 (m, 2H),3.33-3.43 (m, 1H), 3.78-3.87 (m, 1H), 4.03-4.12 (m, 1H), 4.14-4.23 (m,1H), 5.09 (s, 2H), 6.88 (d, J=2.4 Hz, 1H), 6.97 (dd, J=8.8, 2.5 Hz, 1H),7.48 (d, J=8.2 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H),7.68 (s, 1H).

Example 1.7 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 5)

2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (0.051 g, 0.111 mmol) was dissolved in anhydrous DCM (2.0 mL). Thereaction was cooled to 0° C. and N-fluoropyridinium triflate (0.029 g,0.105 mmol) was added. The reaction was stirred at 0° C. for 1 h andthen allowed to warm to 25° C. After 5 h at 25° C., the reaction wascooled to 0° C., additional N-fluoropyridinium triflate (4 mg, 0.01mmol) was added and the reaction was allowed to warm to 25° C. After 5h, the reaction was diluted with EtOAc (50 mL), washed with water (10mL×2), brine (10 mL), dried over MgSO₄ and concentrated under vacuum.The oily residue was purified by silica gel flash column chromatographyto give an oil (0.015 g). The oil was dissolved in DCM and co-evaporatedwith an excess of hexanes to give the title compound as a white solid.LCMS m/z=476.3 [M+F1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66 (d, J=6.69Hz, 4H), 1.84 (d, J=2.53 Hz, 2H), 1.94-2.06 (m, 3H), 2.19-2.30 (m, 1H),2.54-2.63 (m, 1H), 2.71-2.82 (m, 2H), 3.67-3.77 (m, 1H), 3.91-4.01 (m,1H), 4.06-4.15 (m, 1H), 5.16 (s, 2H), 6.83 (dd, J=8.84, 2.40 Hz, 1H),7.02 (d, J=2.27 Hz, 1H), 7.22 (dd, J=8.97, 2.27 Hz, 1H), 7.60-7.66 (m,1H), 7.68-7.74 (m, 2H), 12.31 (bs, 1H).

Resolution Via Chiral HPLC

Column: normal phase preparative Chiralcel IC, 20×250 mm ID, 5 μmparticle sizeEluent: 50:50 MTBE:Hexane with no trifluoroacetic acid

Gradient: Isocratic

Flow: 12 mL/minute

Detector: 280 nm

Retention Times: 1^(st) enantiomer: 12 min; 2^(nd) enantiomer: 16 min

Example 1.8 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 10)

From2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid and 1-iodopyrrolidine-2,5-dione, in a similar manner to the onedescribed in Example 1.4, the title compound was obtained as a brownsolid. LCMS m/z=584.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) 5 ppm 1.55-1.73(m, 4H), 1.78-1.89 (m, 2H), 1.94-2.06 (m, 2H), 2.25-2.37 (m, 1H),2.45-2.58 (m, 1H), 2.77-2.90 (m, 1H), 3.00 (dd, J=16.36, 3.35 Hz, 1H),3.20-3.29 (m, 1H), 3.52-3.61 (m, 1H), 4.00-4.10 (m, 1H), 4.13-4.23 (m,1H), 5.18 (s, 2H), 6.80 (d, J=2.40 Hz, 1H), 6.87 (dd, J=8.78, 2.34 Hz,1H), 7.26 (d, J=8.72 Hz, 1H), 7.63 (d, J=8.08 Hz, 1H), 7.70-7.78 (m,2H), 12.30 (bs, 1H).

Example 1.9 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 1) Step A: Preparation of tert-Butyl2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(100 mg, 0.195 mmol) in DCM (2 mL) was added 1-iodopyrrolidine-2,5-dione(43.8 mg, 0.195 mmol) at 0° C. and the reaction was allowed to continueat 0° C. for 30 min in a 20 mL sealed scintillation vial. After 30 min,the reaction mixture was diluted with DCM, washed with water (3×10 mL),sodium thiolsulfate pentahydrate (aq) (2×10 mL), dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure to givethe title compound as an off-white solid (118 mg). LCMS m/z 640.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (s, 9H), 1.55-1.73 (m, 4H),1.79-1.89 (m, 2H), 1.95-2.05 (m, 2H), 2.26-2.38 (m, 1H), 2.51-2.56 (m,1H), 2.77-2.88 (m, 1H), 2.94 (dd, J=15.92, 3.41 Hz, 1H), 3.20-3.28 (m,1H), 3.50-3.60 (m, 1H), 3.99-4.08 (m, 1H), 4.12-4.21 (m, 1H), 5.18 (s,2H), 6.79 (d, J=2.27 Hz, 1H), 6.87 (dd, J=8.78, 2.46 Hz, 1H), 7.26 (d,J=8.84 Hz, 1H), 7.63 (d, J=8.59 Hz, 1H), 7.70-7.77 (m, 2H).

Step B: Preparation of tert-Butyl2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(50.0 mg, 0.078 mmol) in THF (1 mL) in a heavy-walled sealed microwavetube (0.5-2.0 mL) under N₂ was added methylzinc(H) chloride (2.0 M inTHF, 0.055 mL, 0.109 mmol) and bis(tri-t-butylphosphine)palladium(0)(3.60 mg, 7.04 μmol). The reaction mixture was then heated to 70° C. for2 h, quenched with saturated NaHCO₃ and filtered by vacuum filtrationthrough a pad of Celite®. The pad of Celite® was washed with EtOAc (2×5mL). The filtrate was extracted with EtOAc (3×5 mL). The organic layerswere combined and washed with saturated NaCl (1×10 mL), dried over MgSO₄and filtered by vacuum filtration. The filtrate was concentrated underreduced pressure. The residue was purified by preparative TLC to givethe title compound as a colorless oil (21.1 mg). LCMS m/z=528.3 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (s, 9H), 1.56-1.66 (m, 2H), 1.68-1.79(m, 2H), 1.81-1.92 (m, 2H), 2.04-2.15 (m, 2H), 2.23 (s, 3H), 2.26-2.36(m, 1H), 2.41 (dd, J=15.66, 10.11 Hz, 1H), 2.78-2.90 (m, 2H), 3.31-3.44(m, 1H), 3.65-3.74 (m, 1H), 3.90-3.98 (m, 1H), 3.99-4.12 (m, 1H), 5.09(s, 2H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.03 (d, J=2.15 Hz, 1H), 7.09(d, J=8.72 Hz, 1H), 7.47 (d, J=8.08 Hz, 1H), 7.60 (d, J=8.21 Hz, 1H),7.71 (d, J=1.39 Hz, 1H).

Step C: Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a] indol-1-yl)acetic Acid

tert-Butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(17.5 mg, 0.033 mmol) was added to a solution of2-amino-3-mercaptopropanoic acid (4.02 mg, 0.033 mmol) in TFA (1 mL) andwere stirred at 23° C. for 15 min in a 20 mL sealed scintillation vial.After 15 min, the reaction mixture was poured into about 4 mL of icewater. A precipitate was formed and collected by vacuum filtration. Thesolid was washed with n-hexane (3×5 mL) and dried (vacuum oven) to givethe title compound as a tan solid (13 mg). LCMS m/z=472.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.54-1.73 (m, 4H), 1.80-1.90 (m, 2H), 1.95-2.05(m, 2H), 2.15 (s, 3H), 2.18-2.30 (m, 1H), 2.42-2.48 (m, 1H), 2.69-2.83(m, 2H), 3.20-3.31 (m, 1H), 3.56-3.66 (m, 1H), 3.87-3.96 (m, 1H),3.98-4.08 (m, 1H), 5.14 (s, 2H), 6.76 (dd, J=8.72, 2.40 Hz, 1H), 7.02(d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.63 (d, J=7.96 Hz, 1H),7.68-7.77 (m, 2H), 12.33 (bs, 1H).

Example 1.10 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 9) Step A: Preparation of tert-Butyl2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(50.0 mg, 0.078 mmol) in THF (1 mL) in a 2.0 mL heavy-walled sealedmicrowave tube under N₂ was added cyclopropylzinc(II) bromide (0.5 Msolution in THF, 0.219 mL, 0.109 mmol) andbis(tri-t-butylphosphine)palladium(0) (3.60 mg, 7.04 μmol). The reactionmixture was heated to 70° C. for 2 h, quenched with saturated NaHCO₃ andfiltered by vacuum filtration through Celite®. The Celite® was washedwith EtOAc (2×5 mL). The filtrate was extracted with EtOAc (3×5 mL). Theorganic layers were combined and washed with saturated NaCl (10 mL),dried over MgSO₄, filtered by vacuum filtration. The filtrate wasconcentrated under reduced pressure. The residue was purified bypreparative TLC to give the title compound as a amber oil (9.2 mg). LCMSm/z=554.6 [M+H]⁺.

Step B: Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

tert-Butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(9.2 mg, 0.017 mmol) was added to a solution of2-amino-3-mercaptopropanoic acid (2.013 mg, 0.017 mmol) in TFA (1 mL)and the resulting mixture was stirred at room temperature for 15 min ina 20 mL sealed scintillation vial. After 15 min, the reaction mixturewas poured into approximately 4 mL of ice water. A precipitate formedand was collected by vacuum filtration. The solid was washed withn-hexane (3×5 mL) and dried (vacuum oven) to give the title compound asa off-white solid (5.5 mg). LCMS m/z=498.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.35-0.43 (m, 1H), 0.55-0.64 (m, 1H), 0.74-0.88 (m, 2H),1.55-1.78 (m, 5H), 1.79-1.89 (m, 2H), 1.94-2.05 (m, 2H), 2.19-2.30 (m,1H), 2.42-2.48 (m, 1H), 2.69-2.81 (m, 1H), 2.93 (dd, J=15.92, 3.79 Hz,1H), 120-3.30 (m, 1H), 3.54-3.65 (m, 1H), 3.84-3.94 (m, 1H), 3.97-4.07(m, 1H), 5.15 (s, 2H), 6.76 (dd, J=8.59, 2.27 Hz, 1H), 7.05 (d, J=2.27Hz, 1H), 7.14 (d, J=8.59 Hz, 1H), 7.62 (d, J=8.33 Hz, 1H), 7.67-7.77 (m,2H), 12.28 (bs, 1H).

Example 1.11 Preparation of an Enantiomer of2-(9-Chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 8)

A solution of the 1^(St) enantiomer obtained during the resolution ofCompound 6 by chiral HPLC (described as the enantiomer isolated andhaving the retention time of 6.7 min per the conditions reported inExample 1.2) (20 mg, 0.049 mmol) in DCM (0.500 mL) was cooled to 0° C.NCS (6.60 mg, 0.049 mmol) was added and the reaction was allowed tocontinue at 0° C. for 15 min in a 20 mL sealed scintillation vial. After15 min, the reaction mixture was diluted with DCM and washed with water(2×10 mL), then washed with sodium thiosulfate pentahydrate (aq) (2×10mL), dried over MgSO₄ and filtered by vacuum filtration. The filtratewas concentrated under reduced pressure to give an enantiomer ofCompound 8 as a yellow solid (16.7 mg). LCMS m/z=439.8 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.32 (d, J=5.94 Hz, 6H), 2.25-2.34 (m, 1H),2.52-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.29, 4.17 Hz, 1H),3.63-3.73 (m, 1H), 3.96-4.04 (m, 1H), 4.12-4.19 (m, 1H), 4.76-4.83 (m,1H), 5.07 (s, 2H), 6.86 (dd, J=8.84, 2.40 Hz, 1H), 6.96 (d, J=2.40 Hz,1H), 7.28 (d, J=3.66 Hz, 1H), 7.30 (d, J=3.66 Hz, 1H), 7.72 (dd, J=8.72,2.27 Hz, 1H), 7.79 (d, J=2.15 Hz, 1H), 12.32 (bs, 1H).

Example 1.12 Preparation of an enantiomer of2-(9-Chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 8)

From the 2^(nd) enantiomer obtained during the resolution of Compound 6by chiral HPLC (described as the enantiomer isolated and having theretention time of 9.2 min per the conditions reported in Example 1.2)(20 mg, 0.049 mmol) in a similar manner to the one described in Example1.11, an enantiomer of Compound 8 was obtained as a yellow solid. LCMSm/z=439.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (d, J=6.06 Hz,6H), 2.24-2.36 (m, 1H), 2.52-2.58 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd,J=16.36, 4.11 Hz, 1H), 3.64-3.73 (m, 1H), 3.95-4.06 (m, 1H), 4.11-4.19(m, 1H), 4.75-4.83 (m, 1H), 5.07 (s, 2H), 6.86 (dd, J=8.84, 2.40 Hz,1H), 6.96 (d, J=2.27 Hz, 1H), 7.28 (d, J=3.54 Hz, 1H), 7.30 (d, J=3.79Hz, 1H), 7.72 (dd, J=8.78, 2.21 Hz, 1H), 7.79 (d, J=2.15 Hz, 1H), 12.32(bs, 1H).

Example 1.13 Preparation of2-(9-Cyclobutyl-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 11) Step A: Preparation of tert-Butyl2-(9-Cyclobutyl-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(50 mg, 0.078 mmol) was dissolved in THF (1.0 mL) in a heavy walledsealed microwave tube (0.5-2.0 mL) under N₂. Cyclobutylzinc(II) bromide(0.156 mL, 0.078 mmol) and bis(tri-t-butylphosphine)palladium(0) (3.60mg, 7.04 μmol) were added. The reaction mixture was heated to 70° C. for2 h, quenched with saturated NaHCO₃ and filtered through Celite®. Thefiltrate was then extracted with EtOAc (3×5 mL). The organic layers werecombined and washed with saturated NaCl (10 mL), dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by preparative TLC to provide the title compound asan amber oil (17.3 mg). LCMS m/z=568.8 [M+H]⁺.

Step B: Preparation of2-(9-Cyclobutyl-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

tert-Butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclobutyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(17.2 mg, 0.031 mmol) was added to a solution of2-amino-3-mercaptopropanoic acid (3.76 mg, 0.031 mmol) in TFA (1 mL) andwere stirred at 23° C. for 15 min in a 20 mL sealed scintillation vial.After 15 min, the reaction mixture was poured into about 4 mL of icewater. The product precipitated and was collected by vacuum filtration.The solid was washed with n-hexane (3×5 mL) and dried (vacuum oven) togive the title compound as an off-white solid (6.7 mg). LCMS m/z=512.5[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53-1.72 (m, 4H), 1.80-1.91 (m,3H), 1.93-2.04 (m, 3H), 2.17-2.36 (m, 5H), 2.39-2.48 (m, 1H), 2.63 (dd,J=15.98, 3.98 Hz, 1H), 2.69-2.78 (m, 1H), 3.19-3.28 (m, 1H), 3.57-3.69(m, 2H), 3.90-4.02 (m, 2H), 5.16 (s, 2H), 6.76 (dd, J=8.72, 2.40 Hz,1H), 7.07 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.62 (d, J=8.09Hz, 1H), 7.67-7.76 (m, 2H), 12.26 (bs, 1H).

Example 1.14 Preparation of2-(7-(3-Cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 13) Step A: Preparation of tert-Butyl2-(7-(3-Cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (40 mg,0.139 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (35.8 mg,0.153 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate(54.4 mg, 0.167 mmol). The mixture was stirred at 50° C. for 16 h. Themixture was cooled to room temperature, diluted with ethyl acetate andfiltered through Celite®. The filtrate was concentrated under vacuum andpurified by silica gel column chromatography to provide the titlecompound as an off-white foam (57.4 mg). LCMS m/z=485.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) α ppm 1.24-1.34 (m, 1H), 1.43-1.53 (m, 4H), 1.50 (s,9H), 1.80 (dd, J=12.88, 1.26 Hz, 1H), 1.89 (t, J=10.86 Hz, 4H),2.22-2.34 (m, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79,6.44 Hz, 1H), 2.82-2.92 (m, 1H), 2.99 (t, J=3.09 Hz, 1H), 3.65-3.75 (m,1H), 3.95-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.06 (s, 2H), 6.09 (s, 1H),6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72Hz, 1H), 7.37 (d, J=8.08 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71(d, J=1.52 Hz, 1H).

Step B: Preparation of2-(7-(3-Cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To tert-butyl2-(7-(3-cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(51.4 mg, 0.106 mmol) was added a solution of DL-cysteine (19.87 mg,0.159 mmol) in trifluoroacetic acid (1 mL). The mixture was stirred atroom temperature for 15 min. The reaction mixture was poured into an icewater to form a solid. The solid was filtered and washed with water toprovide the title compound as an off-white solid (41.8 mg). LCMSm/z=429.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) α ppm 1.19-1.31 (m, 1H),1.32-1.55 (m, 4H), 1.69-1.75 (m, 1H), 1.75-1.85 (m, 4H), 2.14-2.25 (m,1H), 2.56 (dd, J=12.00, 8.00 Hz, 1H), 2.67 (dd, J=12.00, 8.00 Hz, 1H),2.71-2.78 (m, 1H), 2.79-2.90 (m, 1H), 3.57 (t, J=7.39 Hz, 1H), 3.87-3.99(m, 1H), 4.02-4.16 (m, 1H), 5.08 (s, 2H), 6.00 (s, 1H), 6.76 (dd,J=8.72, 2.40 Hz, 1H), 7.05 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H),7.51 (d, J=8.21 Hz, 1H), 7.72 (dd, J=8.21, 1.64 Hz, 1H), 7.81 (d, J=1.52Hz, 1H), 12.26 (bs, 1H).

Example 1.15 Preparation of2-(7-(4-Isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 4) Step A: Preparation of tert-Butyl2-(7-(4-Isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.04 g, 0.139 mmol) was dissolved in DMF (1.0 mL) and cesium carbonate(0.045 g, 0.139 mmol) and4-(chloromethyl)-1-isobutyl-2-(trifluoromethyl)benzene (0.035 g, 0.139mmol) was added. The reaction mixture was stirred at room temperaturefor 48 h and then filtered through Celite®. The filtrate was partitionedbetween EtOAc and water. The aqueous layer was extracted two additionaltimes with EtOAc and the combined extracts were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to provide the titlecompound (58 mg). LCMS m/z=502.6 [M+H]⁺.

Step B: Preparation of2-(7-(4-Isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

A solution of 2-amino-3-mercaptopropanoic acid (0.042 g, 0.347 mmol) inTFA (600 μL, 7.79 mmol) was added to neat tert-butyl2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.058 g, 0.116 mmol). The reaction mixture was stirred for 1 h at roomtemperature and then diluted with ice and water causing a tan solid toprecipitate. The aqueous mixture was decanted off of the tan solid andthe solid was rinsed with water. The solid was dried under vacuum togive the title compound (37 mg). LCMS m/z=446.7 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 0.89 (d, J=6.6 Hz, 6H), 1.87-1.98 (m, 1H), 2.16-2.26 (m,1H), 2.53-2.82 (m, 5H), 3.53-3.62 (m, 1H), 3.92-4.00 (m, 1H), 4.06-4.14(m, 1H), 5.13 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.7, 2.4 Hz, 1H), 7.07(d, J=2.3 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.67(d, J=8.1 Hz, 1H), 7.75 (d, J=1.1 Hz, 1H).

Example 1.16 Preparation of2-(7-(4-Chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 17) Step A: Preparation of tert-Butyl2-(7-(4-Chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.053 g,0.183 mmol) in DMF (1 mL) was added Cs₂CO₃ (0.0.071 g, 0.219 mmol)followed by 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (0.050g, 0.183 mmol). The reaction was stirred at 60° C. for 16 h. The mixturewas filtered. The filtrate was concentrated under vacuum and purified bysilica gel column chromatography to give the title compound as a whitesolid (0.048 g). LCMS m/z=480.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm1.49 (s, 9H), 2.21-2.34 (On, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73(dd, J=15.79, 6.32 Hz, 1H), 2.81-2.93 (m, 1H), 3.64-3.77 (m, 1H),3.94-4.05 (m, 1H), 4.06-4.17 (On, 1H), 5.10 (s, 2H), 6.84 (dd, J=8.72,2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H),7.47-7.53 (m, 1H), 7.55-7.61 (m, 1H), 7.79 (s, 1H).

Step B: Preparation of2-(7-(4-Chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To a solution of D,L-cysteine (0.056 g, 0.460 mmol) in TFA (0.9 mL) wasadded tert-butyl2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.079 g, 0.153 mmol). The reaction was stirred for 2 h and poured intoice water. The resulting precipitate was collected by vacuum filtrationto give the title compound as a solid.

LCMS m/z=424.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.14-2.27 (m,1H), 2.55 (dd, J=16.29, 7.96 Hz, 1H), 2.64-2.72 (m, 1H), 2.72-2.82 (m,1H), 3.51-3.64 (m, 1H), 3.90-4.01 (m, 1H), 4.05-4.17 (m, 1H), 5.18 (s,2H), 6.01 (s, 1H), 6.78 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz,1H), 7.20 (d, J=8.72 Hz, 1H), 7.69-7.81 (m, 2H), 7.92 (s, 1H), 12.24(bs, 1H).

Example 1.17 Preparation of2-(7-(4-Cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 18) Step A: Preparation of tert-Butyl2-(7-(4-Cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

From 4-(chloromethyl)-2-(trifluoromethyl)benzonitrile, the titlecompound was prepared as a solid using a similar method to the onedescribed in Example 1.16, Step A. LCMS m/z=471.2 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.49 (s, 9H), 2.22-2.34 (m, 1H), 2.50 (dd, J=15.73,8.27 Hz, 1H), 2.73 (dd, J=15.79, 6.44 Hz, 1H), 2.80-2.93 (m, 1H),3.65-3.77 (m, 1H), 3.95-4.05 (m, 1H), 4.07-4.17 (m, 1H), 5.20 (s, 2H),6.85 (dd, J=8.59, 2.40 Hz, 1H), 7.06 (d, J=2.27 Hz, 1H), 7.15 (d, J=8.84Hz, 1H), 7.74-7.81 (m, 1H), 7.82-7.87 (m, 1H), 7.91 (s, 1H).

Step B: Preparation of2-(7-(4-Cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

From tert-Butyl2-(7-(4-Cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate,the title compound was prepared as a solid using a similar method to theone described in Example 1.16, Step B. LCMS m/z=415.4 [M+H]⁺; NMR (400MHz, DMSO-d₆) δ ppm 2.15-2.27 (m, 1H), 2.55 (dd, J=16.17, 7.96 Hz, 1H),2.64-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.53-3.63 (m, 1H), 3.91-4.01 (m,1H), 4.06-4.15 (m, 1H), 5.30 (s, 2H), 6.02 (s, 1H), 6.81 (dd, J=8.72,2.40 Hz, 1H), 7.08 (d, J=2.40 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.96 (d,J=7.83 Hz, 1H), 8.06 (s, 1H), 8.19 (d, J=8.08 Hz, 1H), 12.27 (bs, 1H).

Example 1.18 Preparation of2-(7-(4-Carbamoyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 19)

To a solution of2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid (15.0 mg, 0.036 mmol) in dioxane (1 mL) was added 1 M LiOH (aq)(3.0 mL). The reaction was stirred at 50° C. for 48 h. 1 M HCl (aq) wasadded until pH=3. The mixture was extracted with EtOAc. The organicextract was dried over MgSO₄ and purified by preparative HPLC/MS to givethe title compound as a solid (3.1 mg). LCMS m/z 433.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.14-2.27 (m, 1H), 2.55 (dd, J=16.23, 8.02 Hz,1H), 2.63-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.52-3.63 (m, 1H), 3.90-4.00(m, 1H), 4.04-4.15 (m, 1H), 5.21 (s, 2H), 6.01 (s, 1H), 6.78 (dd,J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H),7.49-7.60 (m, 2H), 7.75 (d, J=7.83 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H),12.28 (bs, 1H).

Example 1.19 Preparation of2-(7-(4-(Cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 20) Step A: Preparation of tert-Butyl2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

From 4-(chloromethyl)-1-(cyclopropylmethoxy)-2-(trifluoromethyl)benzene,the title compound was prepared as a solid using a similar method to theone described in Example 1.16,

Step A. LCMS m/z=516.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.31-0.38(m, 2H), 0.52-0.60 (m, 2H), 1.15-1.30 (m, 1H), 1.44 (s, 9H), 2.13-2.26(m, 1H), 2.53-2.59 (m, 1H), 2.59-2.68 (m, 1H), 2.69-2.82 (m, 1H),3.51-3.63 (m, 1H), 3.90-4.02 (m, 3H), 4.04-4.14 (m, 1H), 5.06 (s, 2H),5.99 (s, 1H), 6.75 (dd, J=8.72, 2.27 Hz, 1H), 7.06 (d, J=2.27 Hz, 1H),7.18 (d, J=8.72 Hz, 1H), 7.23 (d, J=8.34 Hz, 1H), 7.61-7.70 (m, 2H).

Step B: Preparation of2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid

To a solution of tert-butyl2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(48.4 mg, 0.094 mmol) in DCM (1 mL) was added anisole (0.110 mL, 0.939mmol) and TFA (0.209 mL, 2.82 mmol). The reaction mixture was stirredfor 1 hour. The solvent was removed under vacuum. The residue waspurified by preparative HPLC/MS to give the title compound as a solid(3.8 mg). LCMS m/z=460.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.29-0.38 (m, 2H), 0.50-0.61 (m, 2H), 1.14-1.28 (m, 1H), 2.14-2.26 (m,1H), 2.53-2.61 (m, 1H), 2.63-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.52-3.61(m, 1H), 3.89-4.03 (m, 3H), 4.04-4.16 (m, 1H), 5.06 (s, 2H), 6.01 (s,1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.06 (d, J=2.27 Hz, 1H), 7.18 (d,J=8.59 Hz, 1H), 7.24 (d, J=8.08 Hz, 1H), 7.61-7.72 (m, 2H), 12.27 (bs,1H).

Resolution Via Chiral HPLC.

Column: normal phase ChiralPak IA column, 20 mm ID×250 mm L, 5 pinparticle sizeEluent: 20% IPA/hexanes with 0.1% TFA

Gradient: Isocratic

Flow: 10 mL/min

Detector: 280 nm

Retention Times: 1^(st) enantiomer: 17.1 min; 2^(nd) enantiomer: 18.8min

Example 1.20 Preparation of2-(7-(4-(Cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 21) Step A: Preparation of Methyl4-(Cyclohexylmethyl)-3-(trifluoromethyl)benzoate

To a stirred solution of methyl 4-chloro-3-(trifluoromethyl)benzoate(238 mg, 1.0 mmol) and bis(tri-t-butylphosphine)palladium (0) (51 mg,0.10 mmol) in THF (2 mL) was added (cyclohexylmethyl)zinc(II) bromide (6mL, 3.00 mmol) at room temperature. The reaction mixture was heated atreflux for 2 h, quenched with saturated NaHCO₃ solution, and filteredthrough Celite®. The filtrate was extracted with ethyl acetate. Thecombined organics were dried and concentrated, and the residue waspurified by silica gel column chromatography to give the title compound(280 mg) as a colorless oil. LCMS m/z=301.4. ¹H NMR (400 MHz, CDCl₃) δppm 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.62-1.72 (m, 6H), 2.71 (d,J=6.7 Hz, 2H), 3.94 (s, 3H), 7.39 (d, J=8.1 Hz, 1H), 8.10 (dd, J=8.0,1.5 Hz, 1H), 8.30 (d, J=1.4 Hz, 1H).

Step B: Preparation of(4-(Cyclohexylmethyl)-3-(trifluoromethyl)phenyl)methanol

To a stirred solution of methyl4-(cyclohexylmethyl)-3-(trifluoromethyl)benzoate (280 mg, 0.93 mmol) indioxane (8 mL) was added 2 M lithium borohydride in THF solution (0.93mL, 1.86 mmol). The reaction mixture was heated at 80° C. for 2 h,cooled down, poured into water, acidified with 1 M HCl aqueous solutionto pH 4, extracted with ethyl acetate. The combined organics were washedwith saturated NaHCO₃ solution and water, dried and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (190 mg) as colorless oil. NMR (400 MHz, CDCl₃) δ ppm0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.62-1.72 (m, 6H), 2.67 (d, J=6.7Hz, 2H), 4.71 (d, J=5.7 Hz, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.45 (dd, J=8.0and 1.6 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H).

Step C: Preparation of4-(Chloromethyl)-1-(cyclohexylmethyl)-2-(trifluoromethyl)benzene

To a solution of(4-(cyclohexylmethyl)-3-(trifluoromethyl)phenyl)methanol (0.060 g, 0.220mmol) in toluene (2 mL) was added thionyl chloride (1.32 mmol). Thereaction was heated to 75° C. for 3 h and quenched with water at 0° C.The mixture was extracted with hexanes (twice). The combined organicswere washed with saturated NaHCO₃(aq), dried over MgSO₄, andconcentrated to give the title compound as an oil (0.220 mmol). ¹H NMR(400 MHz, CDCl₃) δ ppm 0.91-1.06 (m, 2H), 1.12-1.23 (m, 3H), 1.61-1.74(m, 6H), 2.66 (d, J=6.95 Hz, 2H), 4.59 (s, 2H), 7.30 (d, J=7.96 Hz, 1H),7.47 (d, J=7.96 Hz, 1H), 7.63 (s, 1H).

Step D: Preparation of tert-Butyl2-(7-(4-(Cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.045 g,0.157 mmol) in DMA (1 mL) was added Cs₂CO₃ (0.0.077 g, 0.235 mmol)followed by4-(chloromethyl)-1-(cyclohexylmethyl)-2-(trifluoromethyl)benzene (0.050g, 0.172 mmol). The reaction was stirred at 60° C. for 16 h. The mixturewas filtered. The filtrate was concentrated under vacuum and purified bysilica gel column chromatography to give the title compound as a whitesolid (0.053 g). LCMS m/z=542.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.90-1.03 (m, 2H), 1.09-1.19 (m, 3H), 1.44 (s, 9H), 1.53-1.69 (m, 6H),2.14-2.26 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 3H), 2.71-2.81 (m,1H), 3.53-3.63 (m, 1H), 3.91-3.99 (m, 1H), 4.05-4.14 (m, 1H), 5.12 (s,2H), 5.99 (s, 1H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz,1H), 7.19 (d, J=8.72 Hz, 1H), 7.44 (d, J=7.96 Hz, 1H), 7.65 (d, J=7.96Hz, 1H), 7.73 (s, 1H).

Step E: Preparation of2-(7-(4-(Cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To a solution of tert-butyl2-(7-(4-(cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(50 mg, 0.092 mmol) in DCM (1 mL) was added thioanisole (0.738 mmol) andTFA (1.85 mmol). The reaction mixture was stirred for 3 h. The solventwas removed under vacuum. The residue was purified by preparativeHPLC/MS to give the title compound as a solid (26.1 mg). LCMS m/z=486.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-1.04 (m, 2H), 1.08-1.20 (m,3H), 1.54-1.70 (m, 6H), 2.15-2.26 (m, 1H), 2.55 (dd, J=16.29, 8.08 Hz,1H), 2.62 (d, J=6.44 Hz, 2H), 2.65-2.72 (m, 1H), 2.72-2.83 (m, 1H),3.52-3.63 (m, 1H), 3.91-4.01 (m, 1H), 4.05-4.14 (m, 1H), 5.12 (s, 2H),6.01 (s, 1H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H),7.19 (d, J=8.59 Hz, 1H), 7.44 (d, J=8.08 Hz, 1H), 7.66 (d, J=7.71 Hz,1H), 7.74 (s, 1H), 12.27 (bs, 1H).

Example 1.21 Preparation of2-(7-(4-(Methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 22) Step A: Preparation of tert-Butyl2-(7-(4-(Methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

From 1-(bromomethyl)-4-(methylsulfonyl)benzene, the title compound wasprepared as a solid using a similar method to the one described inExample 1.20, Step B. LCMS m/z=456.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.52-2.59 (m, 1H), 2.59-2.67 (m,1H), 2.71-2.81 (m, 1H), 3.20 (s, 3H), 3.52-3.63 (m, 1H), 3.91-4.00 (m,1H), 4.05-4.14 (m, 1H), 5.22 (s, 2H), 5.99 (s, 1H), 6.79 (dd, J=8.72,2.40 Hz, 1H), 7.08 (d, J=2.40 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H), 7.71 (d,J=8.21 Hz, 2H), 7.93 (d, J=8.34 Hz, 2H).

Step B: Preparation of2-(7-(4-(Methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

From tert-Butyl2-(7-(4-(Methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate,the title compound was prepared as a solid using a similar method to theone described in Example 1.20, Step C. LCMS m/z=400.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.15-2.27 (m, 1H), 2.55 (dd, J=16.23, 8.02 Hz,1H), 2.64-2.71 (m, 1H), 2.72-2.82 (m, 1H), 3.20 (s, 3H), 3.52-3.63 (m,1H), 3.91-4.00 (m, 1H), 4.05-4.14 (m, 1H), 5.22 (s, 2H), 6.01 (s, 1H),6.79 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.20 (d, J=8.72Hz, 1H), 7.71 (d, J=8.34 Hz, 2H), 7.93 (d, J=8.46 Hz, 2H), 12.28 (bs,1H).

Example 1.22 Preparation of2-(7-(2,4-Bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 23) Step A: Preparation of tert-Butyl2-(7-(2,4-Bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

From 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene, the title compoundwas prepared as a solid using a similar method to the one described inExample 1.20, Step B. LCMS m/z=514.3 [M+H]⁺; ¹1⁻¹ NMR (400 MHz, DMSO-d₆)δ ppm 1.44 (s, 9H), 2.17-2.25 (m, 1H), 2.52-2.58 (m, 1H), 2.60-2.67 (m,1H), 2.71-2.81 (m, 1H), 3.53-3.63 (m, 1H), 3.92-4.01 (m, 1H), 4.06-4.15(m, 1H), 5.32 (s, 2H), 6.01 (s, 1H), 6.79 (dd, J=8.78, 2.34 Hz, 1H),7.07 (d, J=2.27 Hz, 1H), 7.22 (d, J=8.72 Hz, 1H), 8.02-8.09 (m, 2H),8.12 (d, 1H).

Step B: Preparation of2-(7-(2,4-Bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

From tert-butyl2-(7-(2,4-Bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate,the title compound was prepared as a solid using a similar method to theone described in Example 1.20, Step C. LCMS m/z=458.3 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.16-2.27 (m, 1H), 2.52-2.59 (m, 1H), 2.64-2.72(m, 1H), 2.72-2.82 (m, 1H), 3.53-3.63 (m, 1H), 3.92-4.01 (m, 1H),4.07-4.15 (m, 1H), 5.32 (s, 2H), 6.03 (s, 1H), 6.79 (dd, J=8.72, 2.40Hz, 1H), 7.06 (d, J=2.40 Hz, 1H), 7.22 (d, J=8.72 Hz, 1H), 8.02-8.09 (m,2H), 8.10-8.14 (m, 1H), 12.28 (bs, 1H).

Example 1.23 Preparation of2-(7-(4-(1H-Pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 24) Step A: Preparation of tert-Butyl2-(7-(4-(1H-Pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

From 1-(4-(bromomethyl)phenyl)-1H-pyrazole, the title compound wasprepared as a solid using a similar method to the one described inExample 1.20, Step B. LCMS m/z=444.4

[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (s, 9H), 2.21-2.33 (m, 1H),2.49 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.32 Hz, 1H),2.80-2.92 (m, 1H), 3.65-3.76 (m, 1H), 3.95-4.04 (m, 1H), 4.06-4.15 (m,1H), 5.12 (s, 2H), 6.46-6.48 (m, 1H), 6.87 (dd, J=8.72, 2.40 Hz, 1H),7.09-7.15 (m, 2H), 7.55 (d, J=8.46 Hz, 2H), 7.68-7.75 (m, 3H), 7.92 (d,J=2.40 Hz, 1H).

Step B: Preparation of2-(7-(4-(1H-Pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid

From tert-Butyl2-(7-(4-(1H-Pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate,the title compound was prepared as a solid using a similar method to theone described in Example 1.20, Step C. LCMS m/z=388.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.14-2.28 (m, 1H), 2.55 (dd, J=16.23, 8.02 Hz,1H), 2.63-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.52-3.63 (m, 1H), 3.89-4.01(m, 1H), 4.04-4.14 (m, 1H), 5.11 (s, 2H), 6.01 (s, 1H), 6.51-6.57 (m,1H), 6.78 (dd, J=8.65, 2.34 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 7.19 (d,J=8.84 Hz, 1H), 7.56 (d, J=8.59 Hz, 2H), 7.74 (d, J=1.77 Hz, 1H), 7.84(d, J=8.59 Hz, 2H), 8.48 (d, J=2.53 Hz, 1H), 12.27 (bs, 1H).

Example 1.24 Preparation of2-(7-(4-(Cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 25) Step A: Preparation of tert-Butyl2-(7-(4-(Cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

From 4-(chloromethyl)-1-(cyclopentyloxy)-2-(trifluoromethyl)benzene, thetitle compound was prepared as a solid using a similar method to the onedescribed in Example 1.20, Step B. LCMS m/z=530.3 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.49 (s, 9H), 1.53 (bs, 2H), 1.63 (bs, 2H), 1.77-1.97(m, 4H), 2.20-2.35 (m, 1H), 2.49 (dd, J=15.79, 8.46 Hz, 1H), 2.73 (dd,J=15.79, 6.44 Hz, 1H), 2.79-2.94 (m, 1H), 3.65-3.76 (m, 1H), 3.93-4.04(m, 1H), 4.06-4.15 (m, 1H), 4.84-4.91 (m, 1H), 5.01 (s, 2H), 6.84 (dd,J=8.72, 2.27 Hz, 1H), 6.98 (d, J=8.46 Hz, 1H), 7.08-7.15 (m, 2H), 7.54(dd, J=8.46, 1.89 Hz, 1H), 7.64 (d, J=1.64 Hz, 1H).

Step B: Preparation of2-(7-(4-(Cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

From tert-Butyl2-(7-(4-(cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate,the title compound was prepared as a solid using a similar method to theone described in Example 1.20, Step C. LCMS m/z=474.6 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.54-1.78 (m, 6H), 1.84-1.96 (m, 2H), 2.15-2.27(m, 1H), 2.51-2.59 (m, 1H), 2.64-2.72 (m, 1H), 2.72-2.82 (m, 1H),3.52-3.63 (m, 1H), 3.90-4.01 (m, 1H), 4.05-4.14 (m, 1H), 4.98-5.03 (m,1H), 5.05 (s, 2H), 6.01 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.06(d, J=2.40 Hz, 1H), 7.18 (d, J=8.59 Hz, 1H), 7.25 (d, J=9.22 Hz, 1H),7.64-7.70 (m, 2H), 12.27 (bs, 1H).

Example 1.25 Preparation of2-(7-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 28) Step A: Preparation of Isopropyl4-isopropoxy-3-(trifluoromethyl)benzoate

To a mixture of 4-hydroxy-3-(trifluoromethyl)benzoic acid (14.55 mmol)and cesium carbonate (43.7 mmol) in DMA (60 mL) was added 2-bromopropane(36.4 mmol). The reaction was stirred at 80° C. for 16 h. The mixturewas filtered through celite and concentrated under vacuum. The residuewas dissolved in EtOAc and washed with water, then brine, then driedover MgSO₄, and filtered. The solvent was removed under vacuum to givethe title compound as a light yellow oil (13.1 mmol). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.36 (d, J=6.32 Hz, 6H), 1.39 (d, J=6.06 Hz, 6H), 4.72(septet, J=6.06 Hz, 1H), 5.24 (septet, J=6.25 Hz, 1H), 7.00 (d, J=8.84Hz, 1H), 7.26 (s, OH), 8.15 (dd, J=8.72, 2.15 Hz, 1H), 8.23 (d, J=2.15Hz, 1H).

Step B: Preparation of (4-Isopropoxy-3-(trifluoromethyl)phenyl)methanol

To a cooled (−78° C.) solution of4-isopropoxy-3-(trifluoromethyl)benzoate (13.1 mmol) in DCM (85 mL)under nitrogen was added 2.0 M solution of LAH (19.0 mmol) by a syringe.The reaction was allowed to return to room temperature and stirred for16 h. The reaction was cooled to 0° C. and quenched with water (0.95 mL)and 10% NaOH (aq) (1.90 mL). The mixture was filtered through Celite®.The filtrate was concentrated under vacuum to give the title compound asan oil (11.27 mmol). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (d, J=6.06 Hz,6H), 4.46 (d, J=5.81 Hz, 2H), 4.75 (septet, J=6.02 Hz, 1H), 5.20 (t,J=5.75 Hz, 1H), 7.23 (d, J=8.46 Hz, 1H), 7.47-7.56 (m, 2H).

Step C: Preparation of4-(Chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene

To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). Thereaction was stirred at 75° C. for 3 h. The mixture was diluted withhexanes, washed with water (twice), saturated NaHCO₃, dried over MgSO₄,and filtered. The solvent was removed under vacuum to give the titlecompound as an oil (10.4 mmol). NMR (400 MHz, DMSO-d₆) δ ppm 1.29 (d,J=6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J=8.46 Hz, 1H), 7.63-7.70(m, 2H).

Step D: Preparation of tert-Butyl2-(7-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a mixture of tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (1.86 mmol)and cesium carbonate (2.8 mmol) in DMA (7.45 mL) was added4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (1.96 mmol).The reaction was stirred at 80° C. for 16 h. The mixture was filteredthrough Celite®. The solvent was removed under vacuum. The residue waspurified by silica gel column chromatography to give the title compoundas a solid. LCMS m/z=504.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d_(b)) δ ppm1.28 (d, J=5.94 Hz, 6H), 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.51-2.58 (m,1H), 2.59-2.67 (m, 1H), 2.71-2.81 (m, 1H), 3.57 (m, 1H), 3.91-3.99 (m,1H), 4.06-4.13 (m, 1H), 4.72-4.83 (m, 1H), 5.05 (s, 2H), 5.99 (s, 1H),6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72Hz, 1H), 7.28 (d, J=9.22 Hz, 1H), 7.62-7.68 (m, 2H).

Step E: Preparation of2-(7-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To a solution of tert-butyl2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.418 g, 0.830 mmol) in dioxanes (10 mL) was added 1.0 M solution ofLiOH (aq, 2.5 mL). The reaction was stirred at 70° C. for 4 h andacidified with 1M HCl (aq) to pH 3.0. The mixture was extracted withEtOAc, dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a yellow solid (137 mg). LCMS m/z=448.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.28 (d, J=5.94 Hz, 6H), 2.15-2.26 (m, 1H), 2.51-2.59 (m,1H), 2.64-2.72 (m, 1H), 2.72-2.82 (m, 1H), 3.53-3.63 (m, 1H), 3.91-4.00(m, 1H), 4.05-4.14 (m, 1H), 4.74-4.82 (m, 1H), 5.05 (s, 2H), 6.01 (s,1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.06 (d, J=2.27 Hz, 1H), 7.18 (d,J=8.84 Hz, 1H), 7.26-7.32 (m, 1H), 7.63-7.69 (m, 2H), 12.28 (bs, 1H).

Resolution Via Chiral HPLC.

Column: normal phase ChiralPak IA column, 20 mm ID×250 mm L, 5 μmparticle sizeEluent: 10% IPA/hexanes with 0.1% TFA

Gradient: Isocratic

Flow: 12 mL/min

Detector: 280 nm

Retention Times: 1^(st) enantiomer: 29.8 min; 2^(nd) enantiomer: 33.1min

Example 1.26 Preparation of 1^(st) Enantiomer of2-(9-Chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 29)

To a solution of the 1^(st) enantiomer (described as the enantiomerisolated and having the retention time of 29.8 min per the conditionsreported in Example 1.25) of2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (0.049 mmol) in DCM (0.5 mL) at 0° C. was added NCS (0.049 mmol).The reaction was stirred for 15 minutes. The mixture was diluted withDCM and washed with water (twice) and saturated sodium thiolsulfate(aq). The organics were dried over Na₂SO₄, filtered, and concentrated togive the title compound as a yellow solid. LCMS m/z=482.3 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.29 (d, J=6.06 Hz, 6H), 2.24-2.35 (m, 1H),2.51-2.59 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.36, 4.11 Hz, 1H),3.62-3.74 (m, 1H), 3.96-4.05 (m, 1H), 4.11-4.19 (m, 1H), 4.74-4.83 (m,1H), 5.10 (s, 2H), 6.86 (dd, J=8.78, 2.34 Hz, 1H), 6.96 (d, J=2.40 Hz,1H), 7.28 (d, J=8.72 Hz, 1H), 7.31 (s, 1H), 7.65-7.72 (m, 2H), 12.35(bs, 1H).

Example 1.27 Preparation of 2^(nd) Enantiomer of2-(9-Chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 29)

From the 2^(nd) enantiomer (described as the enantiomer isolated andhaving the retention time of 33.1 min per the conditions reported inExample 1.25) of2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid, the title compound was prepared as a solid using a similar methodto the one described in Example 1.26. LCMS m/z=482.3 [M+H]⁺; ¹H NMR (400MHz, CD₃CN) δ ppm 1.32 (d, J=6.06 Hz, 6H), 2.29-2.40 (m, 1H), 2.58 (dd,J=16.48, 9.66 Hz, 1H), 2.81-2.93 (m, 1H), 3.06 (dd, J=16.48, 4.23 Hz,1H), 3.68-3.78 (m, 1H), 3.95-4.05 (m, 1H), 4.09-4.19 (m, 1H), 4.69-4.80(m, 1H), 5.08 (s, 2H), 6.86 (dd, J=8.84, 2.40 Hz, 1H), 7.01 (d, J=2.40Hz, 1H), 7.17 (d, J=8.59 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.59-7.65 (m,1H), 7.67 (s, 1H), 9.05 (bs, 1H).

Example 1.28 Preparation of2-(7-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 36) Step A: Preparation of tert-Butyl2-(9-iodo-7-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.722 g, 1.434 mmol) in DCM (24 mL) at 0° C. was added NIS (1.434mmol). After 5 minutes, the reaction was diluted with DCM and washedwith water (twice) and saturated sodium thiolsulfate (aq). The organicswere dried over Na₂SO₄, filtered, and concentrated to give the titlecompound as a light-brown solid. LCMS m/z=630.5 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.29 (d, J=6.06 Hz, 6H), 1.38 (s, 9H), 2.27-2.38 (m, 1H),2.51-2.56 (m, 1H), 2.77-2.89 (m, 1H), 2.94 (dd, J=15.92, 3.41 Hz, 1H),3.51-3.61 (m, 1H), 3.99-4.09 (m, 1H), 4.12-4.21 (m, 1H), 4.74-4.83 (m,1H), 5.10 (s, 2H), 6.78 (d, J=2.27 Hz, 1H), 6.85 (dd, J=8.72, 2.40 Hz,1H), 7.25 (d, J=8.84 Hz, 1H), 7.30 (d, J=8.34 Hz, 1H), 7.66-7.73 (m,2H).

Step B: Preparation of tert-Butyl2-(7-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(9-iodo-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.778 g, 1.236 mmol) in THF (12.3 mL) under nitrogen was added 2 Msolution of dimethylzinc (1.854 mL, 3.71 mmol), followed bybis(tri-t-butylphosphine)Pd(0) (0.057 g, 0.111 mmol). The reaction wasstirred overnight, slowly quenched with saturated NaHCO₃, diluted withEtOAc, and filtered through Celite®. The organics were washed with water(twice), brine, dried over MgSO₄, and filtered. The solvent was removedunder vacuum. The residue was purified by silica gel columnchromatography to give the title compound as a solid (0.366 g). LCMSm/z=518.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (d, J=5.94 Hz,6H), 1.38 (s, 9H), 2.15 (s, 3H), 2.19-2.30 (m, 1H), 2.43-2.48 (m, 1H),2.69-2.81 (m, 2H), 3.54-3.64 (m, 1H), 3.86-3.96 (m, 1H), 3.98-4.07 (m,1H), 4.73-4.84 (m, 1H), 5.07 (s, 2H), 6.74 (dd, J=8.65, 2.34 Hz, 1H),7.00 (d, J=2.27 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.29 (d, J=9.35 Hz,1H), 7.64-7.71 (m, 2H).

Step C: Preparation of2-(7-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To a solution of tert-butyl2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.366 g, 0.707 mmol) in dioxanes was added aq LiOH (3.0 mmol). Thereaction was stirred at 75° C. for 16 h, diluted with EtOAc and washedwith 1M HCl(aq), dried over MgSO₄, filtered, and concentrated. Theresidue was triturated with hexanes to give the title compound as asolid (0.313 g). LCMS m/z=462.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.28 (d, J=5.94 Hz, 6H), 2.15 (s, 3H), 2.19-2.29 (m, 1H), 2.42-2.48 (m,1H), 2.69-2.82 (m, 2H), 3.57-3.65 (m, 1H), 3.86-3.97 (m, 1H), 3.97-4.08(m, 1H), 4.73-4.84 (m, 1H), 5.07 (s, 2H), 6.74 (dd, J=8.72, 2.40 Hz,1H), 7.01 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.59 Hz, 1H), 7.29 (d, J=9.22Hz, 1H), 7.64-7.72 (m, 2H), 12.26 (bs, 1H).

Resolution Via Chiral HPLC.

Column: normal phase ChiralPak IA column, 20 mm ID×250 mm L, 5 μmparticle sizeEluent: 10% IPA/hexanes with 0.1% TFA=

Gradient: Isocratic

Flow: 10 mL/min

Detector: 280 nm

Retention Times: 1^(st) enantiomer: 17.6 min; 2^(nd) enantiomer: 20.7min

Example 1.29 Preparation of 1^(St) Enantiomer of2-(9-Chloro-7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 30)

From the enantiomer (described as the enantiomer isolated and having theretention time of 17.1 minutes per the conditions reported in Example1.19) of24744-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid, the title compound was prepared as a solid using a similar methodto the one described in Example 1.26. LCMS m/z=494.4 [M+H]⁺; ¹H NMR (400MHz, CD₃CN) δ ppm 0.32-0.39 (m, 2H), 0.55-0.63 (m, 2H), 1.20-1.30 (m,1H), 2.28-2.40 (m, 1H), 2.53-2.63 (m, 1H), 2.80-2.92 (m, 1H), 3.05 (dd,J=16.48, 4.23 Hz, 1H), 3.68-3.78 (m, 1H), 3.97 (d, J=6.69 Hz, 2H),3.98-4.04 (m, 1H), 4.09-4.18 (m, 1H), 5.08 (s, 2H), 6.86 (dd, J=8.78,2.46 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.59 Hz, 1H), 7.20 (d,J=8.84 Hz, 1H), 7.64 (d, J=8.46 Hz, 1H), 7.69 (d, J=1.89 Hz, 1H).

Example 1.30 Preparation of 2^(nd) Enantiomer of2-(9-Chloro-7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 30)

From the 2^(nd) enantiomer (described as the enantiomer isolated andhaving the retention time of 18.8 minutes per the conditions reported inExample 1.19) of2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid, the title compound was prepared as a solid using a similar methodto the one described in Example 1.26. LCMS m/z=494.5 [M+H]⁺; ¹H NMR (400MHz, ACETONITRILE-d₃) δ ppm 0.32-0.39 (m, 2H), 0.55-0.62 (m, 2H),1.20-1.30 (m, 1H), 2.29-2.39 (m, 1H), 2.53-2.62 (m, 1H), 2.81-2.92 (m,1H), 3.05 (dd, J=16.55, 4.17 Hz, 1H), 3.68-3.77 (m, 1H), 3.97 (d, J=6.69Hz, 2H), 3.98-4.04 (m, 1H), 4.10-4.18 (m, 1H), 5.08 (s, 2H), 6.86 (dd,J=8.84, 2.40 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.59 Hz, 1H),7.20 (d, J=8.84 Hz, 1H), 7.63 (dd, J=8.40, 1.96 Hz, 1H), 7.69 (d, J=1.89Hz, 1H).

Example 1.31 Preparation of2-(7-(4-(Fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 31) Step A: Preparation of methyl4-(Fluoromethoxy)-3-(trifluoromethyl)benzoate

To a cooled (−78° C.) mixture of methyl4-hydroxy-3-(trifluoromethyl)benzoate (2.45 g, 11.13 mmol) and cesiumcarbonate (5.44 g, 16.7 mmol) in DMF in a pressure vessel was bubbledchlorofluoromethane (7.00 g, 102 mmol). The vessel was sealed and thereaction was stirred at room temperature for 120 h. The reaction wasfiltered through Celite®. The filtrate was diluted with EtOAc, washedwith water (4 times), dried over MgSO₄, filtered and concentrated undervacuum to give the title compound as a solid (2.44 g). LCMS m/z=253.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.88 (s, 3H), 5.98-6.20 (d,J=52.5 Hz, 2H), 7.59 (d, J=8.84 Hz, 1H), 8.18 (d, J=2.02 Hz, 1H), 8.28(dd, J=8.84, 2.15 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −153.52 (s,1F), −61.08 (s, 3F).

Step B: Preparation of(4-(Fluoromethoxy)-3-(trifluoromethyl)phenyl)methanol

To a cooled (−78° C.) solution of methyl4-(fluoromethoxy)-3-(trifluoromethyl)benzoate (2.44 g, 9.68 mmol) in DCMunder nitrogen was added 2.0 M LAH (4.84 mL, 9.68 mmol) by syringed. Thereaction was stirred for 15 min. The reaction was quenched with water(0.484 mL) and 10% NaOH (0.968 mL). The mixture was filtered andconcentrated to give the title compound as an oil (1.84 g). ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.52 (d, J=5.68 Hz, 2H), 5.32 (t, J=5.75 Hz, 1H),5.85-6.08 (d, J=53.44 Hz, 2H), 7.39 (d, J=8.46 Hz, 1H), 7.56-7.69 (m,2H); ¹H NMR (376 MHz, DMSO-d₆) δ ppm −151.41 (s, 1F), −60.26 (s, 3F).

Step C: Preparation of4-(Chloromethyl)-1-(fluoromethoxy)-2-(trifluoromethyl)benzene

(4-(Fluoromethoxy)-3-(trifluoromethyl)phenyl)methanol (1.84 g, 8.21mmol) was dissolved in thionyl chloride (8.09 mL, 111 mmol) and stirredfor 3 h. The reaction was taken up in hexanes and washed with water(twice), saturated NaHCO₃, and water. The organics were dried overMgSO₄, filtered and concentrated under vacuum to give the title compoundas a solid (1.60 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.83 (s, 2H),5.83-6.14 (d, J=53.1 Hz, 2H), 7.46 (d, J=8.46 Hz, 1H), 7.69-7.87 (m,2H).

Step D: Preparation of tert-Butyl2-(7-(4-(Fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

From 4-(chloromethyl)-1-(fluoromethoxy)-2-(trifluoromethyl)benzene, thetitle compound was prepared as a solid using a similar method to the onedescribed in Example 1.25, Step D. LCMS m/z=494.6 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.49 (s, 9H), 2.19-2.34 (m, 1H), 2.49 (dd, J=15.79,8.34 Hz, 1H), 2.73 (dd, J=15.79, 6.44 Hz, 1H), 2.80-2.93 (m, 1H),3.64-3.76 (m, 1H), 3.99 (bs, 1H), 4.06-4.15 (m, 1H), 5.07 (s, 2H),5.68-5.81 (d, J=53.93 Hz, 2H), 6.08 (s, 1H), 6.84 (dd, J=8.72, 2.40 Hz,1H), 7.08 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.27 (d, J=8.46Hz, 1H), 7.63 (dd, J=8.34, 1.77 Hz, 1H), 7.73 (d, J=1.77 Hz, 1H).

Step E: Preparation of2-(7-(4-(Fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid

From tert-Butyl2-(7-(4-(Fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate,the title compound was prepared as a solid using a similar method to theone described in Example 1.28, Step C. LCMS m/z=438.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.15-2.26 (m, 1H), 2.55 (dd, J=16.29, 7.96 Hz,1H), 2.64-2.72 (m, 1H), 2.72-2.82 (m, 1H), 3.53-3.62 (m, 1H), 3.91-4.00(m, 1H), 4.06-4.14 (m, 1H), 5.12 (s, 2H), 5.92-6.05 (d, J=53.28, 2H),6.01 (s, 1H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H),7.19 (d, J=8.59 Hz, 1H), 7.45 (d, J=9.22 Hz, 1H), 7.75-7.81 (m, 2H),12.26 (bs, 1H).

Example 1.32 Preparation of2-(9-Chloro-7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 32)

From2-(7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid, the title compound was prepared as a solid using a similar methodto the one described in Example 1.26. LCMS m/z=472.0 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.22-2.35 (m, 1H), 2.75-2.86 (m, 1H), 2.90 (dd,J=16.11, 3.98 Hz, 1H), 3.62-3.72 (m, 1H), 3.95-4.04 (m, 1H), 4.09-4.19(m, 1H), 5.17 (s, 2H), 5.92-6.06 (d, J=53.27 Hz, 2H), 6.87 (dd, J=8.84,2.40 Hz, 1H), 6.97 (d, J=2.40 Hz, 1H), 7.28 (d, J=8.84 Hz, 1H), 7.46 (d,J=8.34 Hz, 1H), 7.78-7.83 (m, 2H).

Example 1.33 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 1) Step A: Preparation of Methyl2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

Methyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.923 g, 1.54 mmol) was mostly dissolved in anhydrous THF (15.4 mL) togive a turbid suspension which was degassed with N₂ for about 15 min.Bis(tri-t-butylphosphine)Pd(0) (0.071 g, 0.139 mmol) and 2.0 Mmethylzinc chloride in THF (2.318 mL, 4.64 mmol) were added at 25° C.The reaction mixture was sealed and heated at 70° C. to give a darksuspension. After 2 h at 70° C., the reaction mixture was cooled to 25°C., quenched with NaHCO₃ (4 mL), stirred for 5 min, and filtered througha celite pad. The filtrate was diluted with MTBE, washed with H₂O(twice), brine, and dried over MgSO₄. The solvent was evaporated invacuo to give a solid. The solid was dissolved in DCM/hexanes (1:1) andpurified by silica gel column chromatography to give the titled compound(0.582 g) as a white solid. LCMS m/z=486.5 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.58-1.66 (m, 2H), 1.67-1.79 (m, 2H), 1.80-1.91 (m, 2H),2.05-2.14 (m, 2H), 2.23 (s, 3H), 2.26-2.36 (m, 1H), 2.51 (dd, J=−15.92,10.11 Hz, 1H), 2.82-2.90 (m, 1H), 2.94 (dd, J=15.79, 4.67 Hz, 1H),3.32-3.43 (m, 1H), 3.73 (s, 3H), 3.75-3.80 (m, 1H), 3.92-4.01 (m, 1H),4.02-4.10 (m, 1H), 5.09 (s, 2H), 6.86 (dd, J=8.72, 2.40 Hz, 1H), 7.04(d, J=2.27 Hz, 1H), 7.10 (d, J=8.84 Hz, 1H), 7.47 (d, J=8.08 Hz, 1H),7.61 (d, J=8.08 Hz, 1H), 7.71 (s, 1H).

Step B: Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

Methyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate(0.579 g, 1.192 mmol) was dissolved in 1,4-dioxane (10.74 mL). Aqueous1.0 M lithium hydroxide (3.58 mL, 3.58 mmol) was added at 25° C. to givea slightly turbid solution. The reaction mixture was stirred at 60° C.for 1 h and cooled to 25° C. The solvent was evaporated in vacuo at 25°C. to a volume of 4 mL and added 0.5 M citric acid (14 mL) and MTBE (75mL). The mixture was shaken. The organic layer was separated, washedwith H₂O (2×20 mL), brine (20 mL), and dried over MgSO₄. The solvent wasevaporated in vacuo to give the title compound (0.540 g) as whitecrystals. LCMS m/z=472.3 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.55-1.73 (m, 4H), 1.79-1.90 (m, 2H), 2.01 (m, 2H), 2.15 (s, 3H),2.19-2.29 (m, 1H), 2.40-2.48 (m, 1H), 2.70-2.82 (m, 2H), 3.20-3.28 (m,1H), 3.60 (m, 1H), 3.92 (m, 1H), 4.03 (m, 1H), 5.14 (s, 2H), 6.76 (dd,J=8.72, 2.40 Hz, 1H), 7.02 (d, J=2.40 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H),7.63 (d, J=8.00 Hz, 1H), 7.68-7.76 (m, 2H), 12.26 (bs, 1H).

Resolution Via Chiral HPLC.

Column: normal phase ChiralPak IA column, 20 mm ID×250 mm L, 5 μmparticle sizeEluent: 10% IPA/hexanes with 0.1% TFA

Gradient: Isocratic

Flow: 6 mL/minRetention Times: 1^(st) enantiomer: 21.9 min; 2^(nd) enantiomer: 25.3min

Example 1.34 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 16)

The 1^(st) enantiomer (described as the enantiomer isolated and havingthe retention time of 15 min per the conditions reported in Example 1.7)of2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid (0.100 g, 0.219 mmol) was dissolved in anhydrous DCM (2.2 mL) usinga plastic vial. The reaction was cooled to 0° C., and N-fluoropyridiniumtriflate (0.073 g, 0.295 mmol) was added. The reaction was allowed towarm to 25° C. and after 4 h there was a dark solution. The reaction wasdiluted with EtOAc (40 mL), washed with water/brine (2×10 mL), brine (10mL), and dried over MgSO₄. The solvent was evaporated in vacuo. Theresidue was purified by HPLC to give the titled compound (0.011 g) as ayellow solid. LCMS m/z=535.5 [M+H]⁺; ¹H NMR (400 MHz, CD₃CN) δ ppm1.54-1.78 (m, 4H), 1.79-1.92 (m, 2H), 2.05 (dd, J=9.92, 4.48 Hz, 2H),2.43-2.53 (m, 2H), 2.57-2.73 (m, 2H), 3.29-3.41 (m, 1H), 4.09-4.28 (m,3H), 5.17 (d, J=3.54 Hz, 2H), 6.99 (dd, J=8.84, 2.27 Hz, 1H), 7.34 (d,J=8.84 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.53 (t, J=6.25 Hz, 1H),7.56-7.61 (m, 1H), 7.64-7.69 (m, 1H), 7.73 (s, 1H), 7.90 (d, J=8.34 Hz,1H), 8.23 (td, J=7.86, 1.58 Hz, 1H), 8.66 (d, J=4.42 Hz, 1H).

Example 1.35 Preparation of2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 15) Step A: Preparation of tert-Butyl2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of tert-butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(17 mg, 0.027 mmol) in THF (0.500 mL) in a 0.5-2.0 mL heavy-walledmicrowave sealed tube under N₂ was added diethylzinc (0.074 mL, 0.037mmol) and bis(tri-t-butylphosphine)palladium(0) (1.223 mg, 2.393 μmol).The reaction was then heated to 70° C. for 2 h. The reaction mixture wasquenched with saturated NaHCO₃, filtered by vacuum filtration throughCelite®, and washed with EtOAc (2×5 mL). The filtrate was then extractedwith EtOAc (3×5 mL). The organic layers were combined and washed withsaturated NaCl (1×10 mL), dried (MgSO₄), and filtered by vacuumfiltration through a glass fiber paper. The solvent was removed underreduced pressure. The residue was purified by preparative TLC to givethe title compound (6.6 mg) as an amber oil. LCMS m/z=542.6 [M+H]⁺.

Step B: Preparation2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

tert-Butyl2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(6.6 mg, 0.012 mmol) was added to a solution of2-amino-3-mercaptopropanoic acid (1.476 mg, 0.012 mmol) in TFA (1 mL).The reaction was stirred at 23° C. for 15 min in a 20 mL sealedscintillation vial. The mixture was poured into about 4 mL of ice water.The precipitate was collected by vacuum filtration through a glass fiberpaper, washed with n-hexane (3×5 mL), and dried (vacuum oven) to givethe title compound (0.8 mg) as a tan solid. LCMS m/z=486.3 [M+H]⁺; ¹HNMR (400 MHz, CD₃CN) δ ppm 1.09 (t, J=7.52 Hz, 3H), 1.48-1.59 (m, 2H),1.60-1.69 (m, 2H), 1.74-1.82 (m, 2H), 1.93-2.00 (m, 2H), 2.17-2.27 (m,1H), 2.39-2.49 (m, 1H), 2.55-2.63 (m, 2H), 2.66-2.81 (m, 2H), 3.21-3.32(m, 1H), 3.54-3.63 (m, 1H), 3.82-3.89 (m, 1H), 3.92-4.00 (m, 1H), 5.05(s, 2H), 6.70 (dd, J=8.72, 2.40 Hz, 1H), 6.96 (d, J=2.27 Hz, 1H), 7.03(d, J=8.72 Hz, 1H), 7.49 (d, 1H), 7.57 (d, J=9.35 Hz, 1H), 7.64 (d,J=1.14 Hz, 1H), 8.95 (bs, 1H).

Example 1.36 Preparation of2-(9-Chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 8) Step A: Preparation of tert-Butyl2-(7-(3-Cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.287 g, 1.000 mmol), cesium carbonate (0.489 g, 1.500 mmol) and5-(chloromethyl)-2-isopropoxybenzonitrile (0.315 g, 1.500 mmol) weretaken up in DMF (2.0 mL) and heated to 60° C. for 16 h in a 20 mL sealedscintillation vial. The reaction was cooled down to room temperature andpoured into water and extracted into ether (2×5 mL). The organic layerswere combined and washed with water (3×5 mL), saturated NaCl (1×5 mL),dried over MgSO₄, and filtered by vacuum filtration through a glassfiber paper. The solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound (0.301 g) as a light yellow solid. LCMS m/z=461.5 [M+F1]⁺.

Step B: Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

A solution of 2-amino-3-mercaptopropanoic acid (0.229 g, 1.889 mmol) inTFA (3.15 mL) was made and added to tert-butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.290 g, 0.630 mmol) in a 20 mL sealed scintillation vial and stirredat 23° C. for 15 min. After 15 min the solution was poured into icewater and stirred for 30 minutes. The resulting precipitate wascollected by vacuum filtration, washed with water (2×5 mL) and n-Hexane(3×5 mL), and dried (vacuum oven) to give the title compound (0.202 g)as an off-white solid. LCMS m/z=405.5 [M+H]⁺.

Step C: Preparation of2-(9-Chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-371)aceticAcid

2-(7-(3-Cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (50 mg, 0.124 mmol) was dissolved in DCM (1 mL) and cooled to 0° C.NCS (16.51 mg, 0.124 mmol) was added and the reaction was stirred at 0°C. for 15 min in a 20 mL sealed scintillation vial. The mixture wasdiluted with DCM and washed with water (2×10 mL), Na₂S₂O₃ (aq) (2×10mL), dried over MgSO₄, and filtered by vacuum filtration through a glassfiber paper. The solvent was removed under reduced pressure to give thetitle compound (50.1 mg) as a yellow solid. LCMS m/z=439.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) ppm 1.32 (d, J=6.06 Hz, 6H), 2.24-2.35 (m, 1H),2.52-2.59 (m, 1H), 2.77-2.87 (m, 1H), 2.94 (dd, J=16.29, 4.04 Hz, 1H),3.64-3.73 (m 1H), 3.96-4.07 (m, 1H), 4.10-4.20 (m, 1H), 4.79 (dt,J=12.09, 6.02 Hz, 1H), 5.07 (s, 2H), 6.86 (dd, J=8.72, 2.40 Hz, 1H),6.96 (d, J=2.27 Hz, 1H), 7.29 (dd, J=8.84, 3.79 Hz, 2H), 7.72 (dd,J=8.78, 2.21 Hz, 1H), 7.79 (d, J=2.15 Hz, 1H), 12.35 (s, 1H).

Example 1.37 Preparation of2-(2-(3,4-Diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid (Compound 47) Step A: Preparation of Ethyl2-(2-(3,4-Diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(0.100 g, 0.366 mmol), cesium carbonate (0.179 g, 0.549 mmol) and4-(chloromethyl)-1,2-diethoxybenzene (0.118 g, 0.549 mmol) were taken upin DMA (2 mL) and heated to 60° C. for 16 h in a 20 mL sealedscintillation vial. The reaction was cooled down to room temperature andfiltered by vacuum filtration through a glass fiber paper. The solventwas removed under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound (0.103 g) as anoff-white solid. LCMS m/z=452.3 [M+H]⁺.

Step B: Preparation2-(2-(3,4-Diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid

To a solution of ethyl2-(2-(3,4-diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(0.100 g, 0.221 mmol) in 1,4-dioxane (4 mL) was added 1.0 M LiOH (aq)(1.107 mL, 1.107 mmol). The reaction was stirred at 23° C. for 16 h in a20 mL sealed scintillation vial. The mixture was poured into 1 M HCl andextracted with EtOAc (3×5 mL). The organic layers were combined, driedover MgSO₄, and filtered by vacuum filtration through a glass fiberpaper. The solvent was removed under reduced pressure to give the titlecompound (0.0831 g) as a tan solid. LCMS m/z=424.3 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.27-1.36 (m, 6H), 1.49 (d, J=11.37 Hz, 1H),1.87-1.95 (m, 1H), 1.99-2.07 (m, 1H), 2.07-2.16 (m, 1H), 2.40-2.49 (m,1H), 2.77-2.87 (m, 1H), 3.24-3.35 (m, 1H), 3.73-3.84 (m, 1H), 3.96-4.06(m, 4H), 4.07-4.16 (m, 1H), 4.96 (s, 2H), 6.14 (s, 1H), 6.76 (dd,J=8.78, 2.34 Hz, 1H), 6.88-6.96 (m, 2H), 7.01-7.07 (m, 2H), 7.21 (d,J=8.84 Hz, 1H), 12.27 (s, 1H).

Example 1.38 Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 26) Step A: Preparation of tert-Butyl2-(7-(3-Cyano-4-isopropoxybenzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.576 g, 1.251 mmol) was dissolved in DCM (12.51 mL). The reactionmixture was cooled to 0° C., and NIS (0.295 g, 1.313 mmol) was addedwhile stirring. After stirring at 0° C. for 50 min, the reaction mixturewas diluted with MTBE (60 mL), washed with water (2×20 mL), 2 M sodiumthiosulfate (2×12.5 mL), brine (10 mL), and dried over MgSO₄. Thesolvent was evaporated in vacuo to give the title compound as alight-yellow solid (0.723 g) without further purification. LCMSm/z=587.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃CN) δ ppm 1.36 (d, J=6.06 Hz, 6H),1.40 (s, 9H), 2.34-2.45 (m, 1H), 2.52 (dd, J=15.92, 9.85 Hz, 1H), 2.87(dt, J=18.60, 8.45 Hz, 1H), 2.99 (dd, J=15.92, 3.54 Hz, 1H), 3.57-3.65(m, 1H), 4.05 (m, 1H), 4.17 (m, 1H), 4.75 (dt, J=12.13, 6.06 Hz, 1H),5.06 (s, 2H), 6.83-6.85 (m, 1H), 6.85-6.89 (m, 1H), 7.14 (d, J=8.72 Hz,1H), 7.19 (d, J=8.72 Hz, 1H), 7.67 (dd, J=8.72, 2.15 Hz, 1H), 7.70 (d,J=2.15 Hz, 1H).

Step B: Preparation of tert-Butyl2-(7-(3-Cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.717 g, 1.223 mmol) was dissolved in anhydrous THF (12.2 mL, 1.223mmol). The solution was degassed with nitrogen for about 5 min using asyringe needle. Bis(tri-t-butylphosphine)Pd(0) (0.056 g, 0.110 mmol) and2.0 M methylzinc chloride in THF (1.83 mL, 3.67 mmol) were added. Thereaction vessel was purged with nitrogen, sealed, and heated at 70° C.After 2 h, the reaction mixture was cooled to 25° C. and slowly addedsaturated NaHCO₃ (5 mL). After stirring for about 5 min, the reactionwas diluted with EtOAc (20 mL), filtered through a celite pad, and thecelite pad was washed with EtOAc (3×20 mL). The organic layer was washedwith water (2×20 mL), brine (10 mL), and dried over MgSO₄. The solventwas evaporated in vacuo and the residue was purified by silica gelcolumn chromatography to give the title compound as an oil (0.470 g).LCMS m/z=475.4 [M+H]⁺; ¹H NMR (400 MHz, Acetonitrile-d₃) δ ppm 1.36 (d,J=5.94 Hz, 6H), 1.41 (s, 9H), 2.19 (s, 3H), 2.27-2.37 (m, 1H), 2.46 (dd,J=15.66, 9.22 Hz, 1H), 2.72-2.86 (m, 2H), 3.60-3.69 (m, 1H), 3.93 (m,1H), 4.00-4.10 (m, 1H), 4.75 (dt, J=12.13, 6.06 Hz, 1H), 5.03 (s, 2H),6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.11 (d, J=8.72Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.63-7.68 (m, 1H), 7.69 (d, J=2.27 Hz,1H).

Step C: Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To a pre-cooled flask containing tert-butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.308 g, 0.649 mmol) was added a pre-cooled solution ofD/L-2-Amino-3-mercaptopropanoic acid (0.079 g, 0.649 mmol) in TFA (6.49mL, 0.649 mmol) at 0° C. After stirring for 3 h at 0° C., ice-cold water(65 mL) was added. The resulting suspension was diluted with Et₂O (130mL). The organic layer was separated, washed with water (2×30 mL), brine(30 mL), and dried over MgSO₄. The solvent was coevaporated with toluene(25 mL) in vacuo at 25° C. The residue was coevaporated with toluene (20mL) again to give an oil. The oil was dissolved in DCM (5 mL) andcoevaporated with hexanes (25 mL) to give the title compound as a greysolid (0.299 g). LCMS m/z=419.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) α ppm1.32 (d, J=6.06 Hz, 6H), 2.16 (s, 3H), 2.19-2.29 (m, 1H), 2.47 (d,J=6.69 Hz, 1H), 2.70-2.82 (m, 2H), 3.54-3.65 (m, 1H), 3.92 (m, 1H), 4.03(dt, J=8.05, 1.91 Hz, 1H), 4.79 (dt, J=12.13, 6.06 Hz, 1H), 5.04 (s,2H), 6.74 (dd, J=8.72, 2.40 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.13 (d,J=8.72 Hz, 1H), 7.28 (d, J=8.84 Hz, 1H), 7.72 (dd, J=8.78, 2.21 Hz, 1H),7.78 (d, J=2.15 Hz, 1H), 12.27 (bs, 1H).

Resolution Via Chiral HPLC

Column: normal phase ChiralPak IA, 250×20 mm ID, 5 μm particle sizeEluent: 1% MeOH/DCM with 0.1% TFA

Gradient: Isocratic

Flow: 6 mL/minute

Detector: 280 nM

Retention Times: 1^(st) enantiomer: 25 min; 2^(nd) enantiomer: 28 min

Example 1.39 Preparation of2-(2-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyridoindol-9-yl)acetic Acid (Compound 45) Step A: Preparation of Ethyl2-(2-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(0.107 g, 0.391 mmol) was dissolved in anhydrous DMF (3.91 mL, 0.391mmol). Cesium carbonate (0.166 g, 0.509 mmol) was added followed by4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (0.122 mL,0.587 mmol) to give a suspension. The reaction was heated at 50° C. for5 h. The solvent was evaporated in vacuo to give a residue which wasdissolved in EtOAc (50 mL) and water (20 mL). The organic layer waswashed with water (20 mL), brine (20 mL), and dried over MgSO₄. Thesolvent was evaporated in vacuo to give an oil which was purified bysilica gel column chromatography to give the title compound as an oil(0.154 g). LCMS m/z=490.4 [M+H]⁺; ¹H NMR (400 MHz, Acetonitrile-d₃) αppm 1.24 (t, J=7.14 Hz, 3H), 1.32 (d, J=6.06 Hz, 6H), 1.50-1.64 (m, 1H),2.1 (m, 3H), 2.55 (dd, J=15.73, 8.02 Hz, 1H), 2.86 (dd, J=15.66, 5.94Hz, 1H), 3.33-3.47 (m, 1H), 3.79-3.88 (m, 1H), 4.06-4.21 (m, 3H), 4.74(dt, J=12.09, 6.02 Hz, 1H), 5.04 (s, 2H), 6.13 (s, 1H), 6.81 (dd,J=8.78, 2.46 Hz, 1H), 7.04 (d, J=2.40 Hz, 1H), 7.16 (d, J=8.59 Hz, 1H),7.19 (d, J=8.84 Hz, 1H), 7.62 (d, J=8.59 Hz, 1H), 7.66 (d, J=1.89 Hz,1H).

Step B: Preparation of2-(2-(4-Isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyridoindol-9-yl)acetic Acid

Ethyl2-(2-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(0.147 g, 0.3 mmol) was dissolved in 1,4-dioxane (4.5 mL). LiOH (1.0 M,1.501 mL) was added at 25° C. to give a slightly turbid solution. Thereaction was heated at 50° C. for 2 h, cooled to 24° C., and acidifiedwith 0.5 M citric acid (6.01 mL, 3.00 mmol). The mixture was dilutedwith EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL), anddried over MgSO₄. The solvent was evaporated in vacuo to give an oilwhich was coevaporated with DCM and hexanes (excess) at 25° C. to givethe title compound as an off-white solid (147 mg). LCMS m/z=462.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (d, J=6.06 Hz, 6H),1.39-1.57 (m, 1H), 1.83-2.20 (m, 3H), 2.40-2.48 (m, 2H), 2.84 (dd,J=15.85, 5.62 Hz, 1H), 3.73-3.86 (m, 1H), 4.11 (m., 1H), 4.78 (dt,J=12.16, 6.11 Hz, 1H), 5.06 (s, 2H), 6.15 (s, 1H), 6.78 (dd, J=8.72,2.40 Hz, 1H), 7.05 (d, J=2.40 Hz, 1H), 7.23 (d, J=8.72 Hz, 1H), 7.29 (d,J=9.22 Hz, 1H), 7.63-7.70 (m, 2H), 12.27 (bs, 1H).

Resolution Via Chiral HPLC

Column: normal phase ChiralPak IA, 250×20 mm ID, 5 μm particle size

Eluent: 30% IPA/hexanes Gradient: Isocratic

Flow: 6 mL/minute

Detector: 280 nM

Retention Times: 1^(st) enantiomer: 35 min; 2^(nd) enantiomer: 40 min

Example 1.40 Preparation of2-(7-(3,4-Diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 38) Step A: Preparation of tert-Butyl2-(7-(3,4-Diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(0.150 g, 0.522 mmol), cesium carbonate (0.255 g, 0.783 mmol) and4-(chloromethyl)-1,2-diethoxybenzene (0.168 g, 0.783 mmol) were taken upin DMA (2 mL) and heated to 60° C. for 16 h in a 20 mL sealedscintillation vial. The mixture was cooled down to room temperature andfiltered by vacuum filtration through a glass fiber paper. The solventwas removed under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound (173.1 mg).

Step B: Preparation of2-(7-(3,4-Diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

tert-Butyl2-(7-(3,4-diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(173.1 mg) was taken up in dioxane (4 mL) and 1.0 M aqueous LiOH (1.11mL) was added. The reaction was stirred at 70° C. 16 h, and stirred at80° C. for an additional 5 h. The mixture was cooled to room temperatureand poured into a separatory funnel containing EtOAc and 1.0 M HCl. Thewater layer was removed and the EtOAc layer was washed with water. Theorganics were dried over sodium sulfate, filtered, and concentratedunder reduced pressure to give title compound (131.4 mg). LCMS m/z=410.4[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28-1.34 (m, 6H), 2.15-2.26 (m,1H), 2.54 (dd, J=16.3, 7.9 Hz, 1H), 2.68 (dd, J=16.3, 6.7 Hz, 1H),2.72-2.82 (m, 1H), 3.53-3.62 (m, 1H), 3.91-4.93 (m, 6H), 4.95 (s, 2H),6.0 (s, 1H), 6.73 (dd, J=8.7, 2.4 Hz, 1H), 6.90-6.96 (m, 2H), 7.02-7.06(m, 2H), 7.17 (d, J=9.0 Hz, 1H), 12.3 (bs, 1H).

Example 1.41 Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 41) Step A: Preparation of Ethyl4-Bromo-5-methoxy-1H-indole-2-carboxylate

To a suspension of ethyl 5-methoxy-1H-indole-2-carboxylate (5 g, 22.81mmol) in acetic acid (100 mL) was added bromine (1.169 mL, 22.81 mmol)slowly at room temperature. The reaction mixture was stirred at roomtemperature for 2 days. The solid was filtered off, washed with aceticacid and hexanes, and dried to give the title compound as a white solid(6.8 g). LCMS m/z=298.6 [M+H]⁺.

Step B: Preparation of Ethyl 5-Methoxy-4-methyl-1H-indole-2-carboxylate

To a reaction mixture of ethyl 4-bromo-5-methoxy-1H-indole-2-carboxylate(1 g, 3.35 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.171 g,0.335 mmol) in THF (10 mL) was added a 2 M solution of methylzinc(II)chloride in THF (5.03 mL, 10.06 mmol) at room temperature. The reactionwas stirred at 65° C. for 2 h, cooled down, and added saturated aqueousNaHCO₃ solution. The solid was filtered off through celite and washedwith ethyl acetate. The filtrate was extracted with ethyl acetate. Thecombined organics were dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as white solid (712 mg). LCMS m/z=234.2 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) α ppm 1.42 (t, J=7.1 Hz, 3H), 2.44 (s, 3H), 3.87 (s,3H), 4.41 (q, J=7.1 Hz, 2H), 7.05 (d, J=9.0 Hz, 1H), 7.19-7.24 (m, 2H),8.81 (s, 1H).

Step C: Preparation of7-Methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one

To a suspension of ethyl 5-methoxy-4-methyl-1H-indole-2-carboxylate (712mg, 3.05 mmol) in toluene (10 mL) was added a 1 M solution of KOtBu inTHF (3.97 mL, 3.97 mmol). The reaction mixture was stirred at roomtemperature for 5 min, methyl acrylate (825 μL, 9.15 mmol) was added.The reaction was stirred at reflux overnight and neutralized with 1 NHCl aqueous solution. The solid was collected and divided into threemicrowave vial. Each was added AcOH (8 mL) and H₂O (1 mL), and heated at180° C. for 15 min under microwave irradiation. The solvent wasevaporated and the residue was purified by silica gel columnchromatography to give the title compound as a yellow solid (500 mg).LCMS m/z=216.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.45 (s, 3H), 3.21(t, J=6.5 Hz, 2H), 3.68 (s, 3H), 4.40 (t, J=6.2 Hz, 2H), 6.98 (s, 1H),7.13 (d, J=9.0 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H).

Step D: Preparation of Ethyl2-(7-Methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.38 mL, 6.97mmol) in DMF (2 mL) was added sodium hydride (60% dispersion in mineraloil) (279 mg, 6.97 mmol) at 0° C. The reaction mixture was stirred for10 min, then 7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one(500 mg, 2.323 mmol) in DMF (6 mL) was added. The reaction mixture waswarmed to room temperature and stirred for 1 h, then heated at 60° C.for 1 h, cooled down, poured into saturated NH₄Cl aqueous solution,extracted with ethyl acetate. The combined organics were washed withwater, dried over anhydrous Na₂SO₄, and concentrated. The residue waspurified by silica gel column chromatography to give the title compound(361 mg). LCMS m/z=286.2 [M+H]⁺.

Step E: Preparation of Ethyl2-(7-Methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

Ethyl2-(7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate(351 mg, 1.23 mmol) was dissolved in EtOAc (6 mL) and ethanol (6 mL),10% Palladium on carbon (120 mg) was added. The reaction was degassedand charged with hydrogen, then stirred at room temperature overnight.The solid was filtered off. The filtrate was concentrated to give thetitle compound (320 mg) as an oil without further purification. LCMSm/z=288.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32 (t, J=7.1 Hz, 3H),2.25-2.32 (m, 1H), 2.40 (s, 3H), 2.58 (dd, J=16.0 and 8.6 Hz, 1H),2.80-2.95 (m, 2H), 3.73-3.80 (m, 1H), 3.85 (s, 3H), 3.95-4.02 (m, 1H),4.06-4.18 (m, 1H), 4.18-4.26 (m, 2H), 6.11 (s, 1H), 6.84 (d, J=8.6 Hz,1H), 7.02 (d, J=8.6 Hz, 1H).

Step F: Preparation of Ethyl2-(7-Hydroxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a stirred solution of ethyl2-(7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(320 mg, 1.114 mmol) in anhydrous DCM (8 mL) was added a 1M solution ofboron tribromide in DCM (3341 μL, 3.34 mmol) at 0° C. under nitrogenprotection. The reaction mixture was stirred at this temperature for 1h, neutralized by addition of saturated NaHCO₃ solution. The organiclayer was separated and washed with water and dried over anhydrousNa₂SO₄. The solvent was evaporated, and the residue was purified bycolumn chromatography to give the title compound (200 mg) as a lightyellow oil. LCMS m/z=274.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32(t, J=7.1 Hz, 3H), 2.25-2.32 (m, 1H), 2.40 (s, 3H), 2.58 (dd, J=16.0,8.5 Hz, 1H), 2.82-2.90 (m, 2H), 3.73-3.80 (m, 1H), 3.95-4.02 (m, 1H),4.05-4.13 (m, 1H), 4.20-4.27 (m, 2H), 4.58 (s, 1H), 6.09 (s, 1H), 6.69(d, J=8.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H).

Step G: Preparation of Ethyl2-(7-(3-Cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

To a solution of ethyl2-(7-hydroxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(100 mg, 0.366 mmol) in DMF (3 mL) was added cesium carbonate (155 mg,0.476 mmol), followed by 5-(chloromethyl)-2-isopropoxybenzonitrile (100mg, 0.476 mmol). The reaction mixture was heated at 65° C. for 15 h andcooled down. The solid was filtered and washed with ethyl acetate. Thecombined solvent was evaporated, and the residue was purified by columnchromatography to give the title compound (130 mg) as a colorless oil.LCMS m/z=447.7 [M+H]⁺; ¹H NMR (400 ME-1z, CDCl₃) δ ppm 1.32 (t, J=7.1Hz, 3H), 1.42 (d, J=6.0 Hz, 6H), 2.25-2.32 (m, 1H), 2.42 (s, 3H), 2.58(dd, J=16.0, 8.4 Hz, 1H), 2.82-2.92 (m, 2H), 3.73-3.80 (m, 1H),3.95-4.02 (m, 1H), 4.08-4.15 (m, 1H), 4.20-4.27 (m, 2H), 4.62-4.69 (m,1H), 4.96 (s, 2H), 6.13 (s, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.6, 2.2 Hz, 1H), 7.63 (d,J=2.1 Hz, 1H).

Step H: Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

To a solution of ethyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(130 mg, 0.291 mmol) in dioxane (2 mL) was added a 1 M LiOH aqueoussolution (1.747 mL, 1.747 mmol). The reaction mixture was stirred atroom temperature for 5 h, acidified to pH 3 with 0.5 M citric acidaqueous solution, and extracted with ethyl acetate. The combinedorganics were washed with water, dried over anhydrous Na₂SO₄, andconcentrated to give the title compound as pink solid (110 mg). LCMSm/z=419.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42 (d, J=6.0 Hz, 6H),2.25-2.35 (m, 1H), 2.41 (s, 3H), 2.67 (dd, J=16.5, 8.5 Hz, 1H),2.88-2.98 (m, 2H), 3.73-3.81 (m, 1H), 3.97-4.04 (m, 1H), 4.10-4.16 (m,1H), 4.62-4.68 (m, 1H), 4.97 (s, 2H), 6.17 (s, 1H), 6.84 (d, J=8.7 Hz,1H), 6.97 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.6,2.2 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H).

Resolution Via Chiral HPLC

Column: normal phase ChiralPak IA column, 20 mm ID×250 mm L, 5 nmparticle sizeEluent: 30% IPA/hexanes with 0.1% TFA

Gradient: Isocratic

Flow: 6 mL/min

Detector: 280 nm

Retention time: 1″ enantiomer: 22.3 min; 2^(nd) enantiomer: 25.0 min

Example 1.42 Preparation of2-(9-Chloro-7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 42)

To a solution of2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (30 mg, 0.072 mmol) in DCM (2 mL) was added N-chlorosuccinimide(10.1 mg, 0.075 mmol) at 0° C. The reaction was stirred at thattemperature for 40 min, diluted with DCM, washed with aqueous Na₂S₂O₃solution and water, and dried over anhydrous Na₂SO₄. The solvent wasevaporated, and the residue was passed through a silica gel column with5% MeOH/DCM to give the title compound as beige solid (23 mg). LCMSm/z=453.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.41 (d, J=6.0 Hz, 6H),2.29-2.38 (m, 1H), 2.58 (dd, J=16.7, 10.5 Hz, 1H), 2.66 (s, 3H),2.88-2.98 (m, 1H), 3.33 (dd, J=16.7, 3.7 Hz, 1H), 3.76-3.84 (m, 1H),3.90-3.98 (m, 1H), 4.05-4.13 (m, 1H), 4.62-4.68 (m, 1H), 4.94 (s, 2H),6.84 (d, J=8.8 Hz, 1H), 6.95-6.98 (m, 2H), 7.56-7.62 (m, 2H).

Example 1.43 Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 43) Step A: Preparation of tert-Butyl2-(7-(3-Cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate

tert-Butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(100 mg, 0.171 mmol) in NMP (2 mL) was added copper(I) iodide (162 mg,0.853 mmol) and sodium methanesulfinate (102 mg, 0.853 mmol). Thereaction mixture was heated at 125° C. under nitrogen protection for 8h. The solid was filtered and washed with ethyl acetate. The filtratewas washed with water and dried over anhydrous Na₂SO₄. The solvent wasevaporated and the residue was purified by column chromatography to givethe title compound (36 mg). LCMS m/z=539.6 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.36 (s, 9H), 1.40 (d, J=6.0 Hz, 6H), 2.46-2.55 (m, 1H),2.74 (dd, J=16.0, 9.0 Hz, 1H), 2.88-2.98 (m, 1H), 3.12 (s, 3H),3.08-3.14 (dd, J=16.0, 3.6 Hz, 1H), 3.95-4.02 (m, 1H), 4.05-4.20 (m,2H), 4.62-4.69 (m, 1H), 5.03 (s, 2H), 6.95 (dd, J=8.8, 2.4 Hz, 1H), 6.98(d, J=8.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.59(dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H),

Step B: Preparation of2-(7-(3-Cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

D/L-Cysteine (40.5 mg, 0.334 mmol) was dissolved in TFA (1 mL) andcooled down to 0° C. The solution was added to a solution of tert-butyl2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(36 mg, 0.067 mmol) in DCM (1 mL) at 0° C. The reaction was stirred atthis temperature for 1 h. Water was added, then ethyl acetate was added.The organic layer was separated, washed with water and brine, dried overanhydrous Na₂SO₄, and concentrated. The residue was purified bypreparative HPLC. The combined fractions were partially concentrated invacuo and diluted with ethyl acetate. The organic layer was separated,washed with water, and dried over anhydrous Na₂SO₄. The solvent wasevaporated to give the title compound as white solid. LCMS m/z=483.3[M+H]⁺; NMR (400 MHz, CDCl₃) δ ppm 1.41 (d, J=6.0 Hz, 6H), 2.46-2.55 (m,1H), 2.84 (dd, J=16.7 and 9.5 Hz, 1H), 2.92-3.03 (m, 1H), 3.11 (s, 3H),3.33 (dd, J=16.7, 3.4 Hz, 1H), 3.98-4.08 (m, 1H), 4.10-4.17 (m, 1H),4.17-4.25 (m, 1H), 4.62-4.69 (m, 1H), 5.04 (s, 2H), 6.95-7.00 (m, 2H),7.22 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.7, 2.2 Hz,1H), 7.66 (d, J=2.2 Hz, 1H).

Example 1.44 Preparation of2-(2-(3-Cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid (Compound 44) Step A: Preparation of5-(Benzyloxy)-1-(4-ethoxy-4-oxobutyl)-1H-indole-2-carboxylate

Ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (10 g, 33.9 mmol) wasdissolved in anhydrous DMF (100 mL), the solution was cooled to 0° C.and slowly added sodium hydride (60% dispersion in mineral oil) (1.80 g,45.0 mmol). The reaction was stirred at 0° C. for 30 min.Tetrabutylammonium iodide (8.50 g, 23.02 mmol) was added at 0° C.followed by addition of ethyl 4-bromobutyrate (7.28 mL, 50.8 mmol). Thereaction mixture was warmed to room temperature and stirred for 16 h.Saturated aqueous NH₄Cl was added. The mixture was extracted with ethylacetate. The combined organics were washed with water, brine and driedover anhydrous MgSO₄. The solvent was evaporated, and the residue waspurified by silica gel column chromatography to give the title compoundas an amber oil (13.46 g). LCMS m/z=410.3 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.18 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H), 2.05 (t,J=7.2 Hz, 2H), 2.20-2.32 (m, 2H), 4.05 (q, J=7.2 Hz, 2H), 4.28 (q, J=7.2Hz, 2H), 4.52 (t, J=7.3 Hz, 2H), 5.03 (s, 2H), 6.99-7.09 (m, 2H), 7.13(s, 1H), 7.19 (s, 1H), 7.21-7.35 (m, 3H), 7.36-7.44 (m, 2H).

Step B: Preparation of Ethyl2-(Benzyloxy)-9-hydroxy-6,7-dihydropyrido[1,2-a]indole-8-carboxylate

To a solution of ethyl5-(benzyloxy)-1-(4-ethoxy-4-oxobutyl)-1H-indole-2-carboxylate (1 g,2.442 mmol) in THF was added a 1 M solution of KOtBu in THF (3.17 mL,3.17 mmol) at 0° C. The reaction mixture was stirred at that temperaturefor 2 h, poured into 1 N HCl aqueous solution, extracted with ethylacetate. The combined organics were washed with water, dried overNa₂SO₄, and concentrated to give the title compound (850 mg) withoutfurther purification. LCMS m/z=364.3 [M+H]⁺.

Step C: Preparation of2-(Benzyloxy)-7,8-dihydropyrido[1,2-a]indol-9(6H)-one

The reaction mixture of ethyl2-(benzyloxy)-9-hydroxy-6,7-dihydropyrido[1,2-a]indole-8-carboxylate(1.22 g, 3.36 mmol) in acetic acid (36 mL) and H₂O (3 mL) was heated at220° C. for 10 min under microwave irradiation. The solvent was removedin vacuo. The residue was purified by silica gel column chromatographyto give the title compound (780 mg) as a yellow solid. LCMS m/z=292.3[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.38-2.45 (m, 2H), 2.73 (t, J=6.4Hz, 2H), 4.23 (t, J=5.9 Hz, 2H), 5.11 (s, 2H), 7.15 (dd, J=8.9, 2.4 Hz,1H), 7.18 (d, J=2.3 Hz, 1H), 7.22 (s, 1H), 7.25-7.30 (m, 1H), 7.30-7.35(m, 1H), 7.36-7.42 (m, 2H), 7.45-7.50 (m, 2H).

Step D: Preparation of Ethyl2-(2-(Benzyloxy)-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (3.11 mL, 15.65mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in mineraloil) (626 mg, 15.65 mmol) at 0° C. The reaction was slowly warmed toroom temperature and stirred for 10 min.2-(Benzyloxy)-7,8-dihydropyrido[1,2-a]indol-9(6H)-one (570 mg, 1.956mmol) in DMF was added. The reaction was heated at 65° C. for 2 h,cooled down, poured into saturated NH₄Cl aqueous solution, and extractedwith ethyl acetate. The combined organics were washed with water, driedover anhydrous Na₂SO₄, and concentrated. The residue was purified bysilica gel column chromatography to give the title compound (608 mg).LCMS m/z=362.5 [M+H]⁺.

Step E: Preparation of Ethyl2-(2-Hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

Ethyl2-(2-(benzyloxy)-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate(608 mg, 1.682 mmol) was dissolved in THF/MeOH (1:1) (4 mL). Ammoniumformate (648 mg, 10.28 mmol) and palladium hydroxide (20 wt % Pd oncarbon) (60 mg) was added under nitrogen protection. The reaction washeated at reflux for 5 h. The solid was filtered. The filtrate wasconcentrated, dissolved in ethyl acetate, washed with water, dried overanhydrous Na₂SO₄, and concentrated. The residue was purified by silicagel column chromatography to give the title compound (402 mg) ascolorless oil. LCMS m/z=274.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32(t, J=7.1 Hz, 3H), 1.50-1.61 (m, 1H), 1.98-2.08 (m, 1H), 2.08-2.22 (m,2H), 2.55 (dd, J=15.6 and 8.7 Hz, 1H), 2.94 (dd, J=15.6, 5.5 Hz, 1H),3.44-3.52 (m, 1H), 3.80-3.88 (m, 1H), 4.07-4.13 (m, 1H), 4.24 (q, J=7.1Hz, 2H), 4.95 (s, 1H), 6.12 (s, 1H), 6.74 (dd, J=8.6, 2.4 Hz, 1H), 6.95(d, J=2.4 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H).

Step F: Preparation of Ethyl2-(2-(3-Cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

To a mixture of ethyl2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (50 mg,0.183 mmol) and cesium carbonate (89 mg, 0.274 mmol) in DMF (2 mL) wasadded 5-(chloromethyl)-2-isopropoxybenzonitrile (46 mg, 0.22 mmol). Thereaction was heated at 75° C. for 5 h and cooled down. The solid wasfiltered and washed with ethyl acetate. The combined solvent wasevaporated, and the residue was purified by silica gel columnchromatography to give the title compound (70 mg). LCMS m/z=447.4[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.40 (d,J=6.1 Hz, 6H), 1.51-1.61 (m, 1H), 1.98-2.08 (m, 1H), 2.08-2.24 (m, 2H),2.55 (dd, J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.4 Hz, 1H), 3.45-3.54(m, 1H), 3.82-3.92 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H),4.61-4.68 (m, 1H), 5.00 (s, 2H), 6.17 (s, 1H), 6.85 (dd, J=8.8, 2.4 Hz,1H), 6.95 (d, J=8.8 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz,1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).

Step G: Preparation of2-(2-(3-Cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid

To a solution of ethyl2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(70 mg, 0.157 mmol) in dioxane (1 mL) was added 1 M LiOH aqueoussolution (0.627 mL, 0.627 mmol). The reaction was stirred at roomtemperature for 8 h, diluted with water, and acidified to pH 4 with 0.5M aqueous citric acid solution. The light pink solid was collected togive the title compound (63 mg). LCMS m/z=419.4 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) 1.40 (d, J=6.1 Hz, 6H), 1.55-1.65 (m, 1H), 1.98-2.12 (m, 1H),2.15-2.25 (m, 2H), 2.65 (dd, J=16.1, 8.6 Hz, 1H), 3.01 (dd, J=−16.1, 5.3Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.92 (m, 1H), 4.12-4.18 (m, 1H),4.61-4.68 (m, 1H), 5.01 (s, 2H), 6.22 (s, 1H), 6.86 (dd, J=8.8, 2.4 Hz,1H), 6.96 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.7 Hz,1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).

Resolution Via Chiral HPLC

Column: normal phase ChiralPak IA column, 20 mm ID×250 mm L, 5 μmparticle size

Eluent: 30% IPA/hexanes Gradient: Isocratic

Flow: 12 mL/min

Detector: 280 nm

Retention time: 1^(st) enantiomer: 25.1 min; 2^(nd) enantiomer: 30.7 min

Example 1.45 Preparation of2-(2-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid (Compound 46) Step A: Preparation of Ethyl2-(2-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

To a mixture of ethyl2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (107 mg,0.391 mmol) and cesium carbonate (191 mg, 0.587 mmol) in DMF (2 mL)wasadded 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (123 mg,0.47 mmol). The reaction was heated at 75° C. for 5 h and cooled down.The solid was filtered and washed with ethyl acetate. The combinedsolvent was evaporated, and the residue was purified by silica gelcolumn chromatography to give the title compound (143 mg). LCMSm/z=500.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32 (t, J=7.1 Hz, 3H),1.52-1.67 (m, 3H), 1.68-1.80 (m, 2H), 1.80-1.92 (m, 2H), 2.00-2.24 (m,5H), 2.55 (dd, J=15.6 and 8.7 Hz, 1H), 2.95 (dd, J=15.6 and 5.4 Hz, 1H),3.35-3.45 (m, 1H), 3.45-3.55 (m, 1H), 3.83-3.92 (m, 1H), 4.10-4.18 (m,1H), 4.23 (q, J=7.1 Hz, 2H), 5.10 (s, 2H), 6.19 (s, 1H), 6.90 (dd, J=8.8and 2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.48(d, J=8.1 Hz, 1H), 7.60 (dd, J=8.1 and 1.3 Hz, 1H), 7.71 (d, J=1.4 Hz,1H).

Step B: Preparation of2-(2-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid

To a solution of ethyl2-(2-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(143 mg, 0.286 mmol) in dioxane (1.5 mL) was added 1 M LiOH aqueoussolution (1.15 mL, 1.145 mmol). The reaction mixture was stirred at 45°C. for 3 h. A portion of the solvent was removed in vacuo. The remainingmixture was diluted with water, acidified with 0.5 M aqueous citric acidto pH 4, and extracted with ethyl acetate. The combined organics werewashed with water, dried over anhydrous Na₂SO₄, and concentrated to givethe title compound (105 mg). LCMS m/z=472.3 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.54-1.66 (m, 3H), 1.67-1.80 (m, 2H), 1.80-1.92 (m, 2H),2.00-2.24 (m, 5H), 2.64 (dd, J=16.1 and 8.7 Hz, 1H), 3.01 (dd, J=16.1and 5.3 Hz, 1H), 3.33-3.42 (m, 1H), 3.45-3.55 (m, 1H), 3.85-3.94 (m,1H), 4.12-4.18 (m, 1H), 5.08 (s, 2H), 6.22 (s, 1H), 6.90 (dd, J=8.8 and2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.47 (d,J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.70 (s, 1H).

Example 1.46 Preparation of2-(2-(3,5-Bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid (Compound 48) Step A: Preparation of Ethyl2-(2-(3,5-Bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

To a mixture of ethyl2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (95 mg,0.348 mmol) and cesium carbonate (170 mg, 0.521 mmol) in DMF (2 mL) wasadded 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (128 mg, 0.417mmol). The reaction mixture was heated at 75° C. for 15 h and cooleddown. The solid was filtered and washed with ethyl acetate. The combinedsolvent was evaporated, and the residue was purified by silica gelcolumn chromatography to give the title compound (145 mg). LCMSm/z=500.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.30 (t, J=7.1 Hz, 3H),1.51-1.61 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.55 (dd,J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.4 Hz, 1H), 3.45-3.54 (m, 1H),3.85-3.94 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 5.19 (s,2H), 6.18 (s, 1H), 6.90 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H),7.18 (d, J=8.7 Hz, 1H), 7.83 (s, 1H), 7.94 (s, 2H).

Step B: Preparation of2-(2-(3,5-Bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid

To a solution of ethyl2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(145 mg, 0.29 mmol) in dioxane (1.5 mL) was added 1 M LiOH aqueoussolution (1.16 mL, 1.161 mmol). The reaction was stirred at roomtemperature for 8 h, diluted with water, and acidified to pH 4 with 0.5M aqueous citric acid. The solid precipitate was collected to give thetitle compound (125 mg). LCMS m/z=471.8 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ ppm 1.55-1.65 (m, 1H), 2.00-2.10 (m, 1H), 2.17-2.26 (m, 2H), 2.65 (dd,J=−16.1, 8.5 Hz, 1H), 3.00 (dd, J=16.1, 5.4 Hz, 1H), 3.45-3.54 (m, 1H),3.85-3.94 (m, 1H), 4.14-4.22 (m, 1H), 5.19 (s, 2H), 6.23 (s, 1H), 6.91(dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.19 (d, J=−8.7 Hz,1H), 7.83 (s, 1H), 7.94 (s, 2H).

Resolution Via Chiral HPLC

Column: normal phase Chiralcel OD, 500×50 mm ID

Eluent: 20% IPA/hexanes Gradient: Isocratic

Flow: 60 mL/min

Detector: 280 nm

Retention time: 1^(st) enantiomer: 29.0 min; 2^(nd) enantiomer: 40.2 min

Example 1.47 Preparation of2-(2-(3-Cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid (Compound 27) Step A: Preparation of Ethyl2-(2-(3-Cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate

To a mixture of ethyl2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (75 mg,0.274 mmol) and cesium carbonate (134 mg, 0.412 mmol) in DMF (2 mL) wasadded 3-(chloromethyl)-5-(trifluoromethoxy)benzonitrile (78 mg, 0.329mmol). The reaction was heated at 75° C. for 15 h and cooled down. Thesolid was filtered and washed with ethyl acetate. The combined solventwas evaporated, and the residue was purified by silica gel columnchromatography to give the title compound (108 mg). LCMS m/z=473.6[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.51-1.62(m, 1H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.55 (dd, J=15.6, 8.6 Hz,1H), 2.93 (dd, J=15.6, 5.5 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.93 (m,1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 5.14 (s, 2H), 6.18 (s,1H), 6.87 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.18 (d,J=8.8 Hz, 1H), 7.44 (s, 1H), 7.58 (s, 1H), 7.71 (s, 1H).

Step B: Preparation of2-(2-(3-Cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticAcid

To a solution of ethyl2-(2-(3-cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate(108 mg, 0.229 mmol) in dioxane (1 mL) was added 1 M LiOH aqueoussolution (0.914 mL, 0.914 mmol). The reaction was stirred at roomtemperature for 8 h, diluted with water, and acidified to pH 4 with 0.5M aqueous citric acid. The solid precipitate was collected to give thetitle compound (90 mg). LCMS m/z=445.3 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) αppm 1.57-1.68 (m, 1H), 2.00-2.14 (m, 1H), 2.16-2.27 (m, 2H), 2.65 (dd,J=16.1, 8.5 Hz, 1H), 3.01 (dd, J=16.1, 5.4 Hz, 1H), 3.46-3.55 (m, 1H),3.85-3.93 (m, 1H), 4.13-4.20 (m, 1H), 5.13 (s, 2H), 6.23 (s, 1H), 6.89(dd, J=8.8, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H),7.44 (s, 1H), 7.58 (s, 1H), 7.70 (s, 1H).

Resolution Via Chiral HPLC

Column: normal phase Chiralcel OD, 500×50 mm ID

Eluent: 45% IPA/hexanes Gradient: Isocratic

Flow: 60 mL/min

Detector: 280 nm

Retention time: 1^(st) enantiomer: 43.1 min; 2^(nd) enantiomer: 55.2 min

Example 1.48 Preparation of2-(7-(3-Cyano-4-cyclopentylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 37) Step A: Preparation of5-(Chloromethyl)-2-cyclopentylbenzonitrile

2-Cyclopentylbenzonitrile (1.3 g, 7.59 mmol) was transferred into a2-necked RB flask, fitted with an addition funnel and dry nitrogeninlet. The starting material was stirred and cooled to −22° C. (dryice/IPA bath). Sulfuric acid (3.25 mL, 61.0 mmol) was added in drops.1,3,5-Trioxane (0.877 mL, 11.39 mmol) was added in 3 batches (Thebatches were added fairly quickly, one after another). Almostimmediately, chlorosulfonic acid (0.915 mL, 13.67 mmol) was added indrops. Then the reaction mixture (dark brown in color) was allowed towarm up to −7° C. (over approx 15 min). It was stirred at between 6.9°C. and −5° C. for 1.5 h. The reaction was quenched by slowly pouringinto ice water. MTBE was added and the mixture was stirred well andfiltered through Celite®. The Celite® bed was washed with MTBE and theaqueous acid layer was separated. The acid layer was extracted withMTBE. The combined MTBE layer was washed with water followed bysaturated NaHCO₃ solution. The organic layer was washed with water untilwashings were neutral to pH paper. The organic layer was dried overanhydrous Na₂SO₄ and filtered. The solvent was removed under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound.

Step B: Preparation of2-(7-(3-Cyano-4-cyclopentylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

5-(Chloromethyl)-2-cyclopentylbenzonitrile (38.2 mg, 0.174 mmol),tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate(50 mg, 0.174 mmol), and K₂CO₃ (36.1 mg, 0.261 mmol) were dissolved inDMF and heated to 60° C. for 16 h. The reaction mixture was filteredthrough Celite® and purified by HPLC. The intermediate was isolated anddissolved in TFA (0.2M) and added D/L-cysteine. After 15 min, themixture was poured into water and extracted with DCM. The organicextract was concentrated to give the title compound. LCMS m/z=415.6[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.55-1.67 (m, 2H), 1.70-1.78 (m,2H), 1.80-1.88 (m, 2H), 2.11-2.20 (m, 2H), 2.26-2.36 (m, 1H), 2.66 (dd,J=16.5, 8.6 Hz, 1H), 2.86-2.97 (m, 2H), 3.42 (quintet, J=8.6 Hz, 1H),3.75 (quintet, J=7.3 Hz, 1H), 3.97-4.05 (m, 1H), 4.10-4.17 (m, 1H), 5.06(s, 2H), 6.12 (s, 1H), 6.85 (dd, J=8.0, 2.0 Hz, 1H), 7.06 (d, J=2.0 Hz,1H), 7.14 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.3 Hz,1H), 7.69 (s, 1H).

Example 1.49 Preparation of2-(9-Chloro-7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 40)

From tert-butyl2-(7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate,the title compound was prepared using a similar method to the onedescribed in Example 1.28, Step A and Example 1.25, Step E. ¹H NMR (400MHz, CDCl₃) δ ppm 2.32-2.41 (m, 1H), 2.60 (dd, J=16.7, 10.3 Hz, 1H),2.92-3.11 (m, 1H), 3.30 (dd, J=16.5, 3.9 Hz, 1H), 3.78-3.86 (m, 1H),3.97-4.05 (m, 1H), 4.11-4.18 (m, 1H), 4.58-4.69 (m, 3H), 4.76-4.79 (m,2H), 5.04 (s, 2H), 6.90 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H),7.09 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.32 (dd, J=8.4, 1.9 Hz,1H), 7.53 (d, J=1.9 Hz, 1H).

Example 1.50 Preparation of2-(7-(3-Chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 39) Step A: Preparation of Methyl3-Chloro-4-(1,3-difluoropropan-2-yloxy)benzoate

To a solution of 1,3-difluoropropan-2-ol (2.57 g, 26.8 mmol) in THF (35mL) was added methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.72 mmol),followed by triphenylphosphine (7.03 g, 26.8 mmol) and DIAD (5.21 mL,26.8 mmol). The reaction was stirred overnight at room temperature,diluted with EtOAc and washed with brine. The organics were separated,washed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography to give the titlecompound (3.743 g) as a clear oil. LCMS m/z=265.1 [M+H]⁺.

Step B: Preparation of 3-Chloro-4-(1,3-difluoropropan-2-yloxy)benzoicAcid

To a solution of methyl 3-chloro-4-(1,3-difluoropropan-2-yloxy)benzoate(2.00 g, 7.56 mmol) in dioxane (15.11 mL) was added LiOH (1.0 M aq,22.67 mL, 22.67 mmol). The reaction was stirred at 30° C. for 1.5 h in a1 L round-bottomed flask. The reaction was cooled to room temperatureand poured into 1 N HCl. A precipitate was formed and filtered by vacuumfiltration to give the title compound (1.5 g) as a white solid. LCMSm/z=250.9 [M+H]⁺.

Step C: Preparation of2-Chloro-4-(chloromethyl)-1-(1,3-difluoropropan-2-yloxy)benzene

To a solution of 3-chloro-4-(1,3-difluoropropan-2-yloxy)benzoic acid(1.5 g, 5.99 mmol) at 0° C. in a round bottomed flask was addedborane-THF (9.88 mL of a 1.0 M soln in THF, 9.88 mmol) slowly over 5min. The mixture was stirred at 0° C. for 30 min at which time theice-bath was removed and the reaction was warmed up to room temp andstirred overnight. The mixture was poured slowly into saturated NaHCO₃solution at 0° C. and extracted with EtOAc (3×200 mL). The organiclayers were combined, dried over MgSO₄, and filtered by vacuumfiltration through a glass fiber paper. The solvent was removed underreduced pressure. The solid was dissolved in toluene (9.13 mL) andthionyl chloride was added (1.999 mL, 27.4 mmol). After 15 min, thereaction mixture was poured into water at 0° C. and extracted into MTBE(2×100 mL). The organic layers were combined and washed with saturatedNaHCO₃ solution (3×100 mL) (caution! gas evolves), dried over MgSO₄,filtered by vacuum filtration through a glass fiber paper and thesolvent was removed under reduced pressure to give the title compound(0.75 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.51 (s, 2H), 4.60-4.70 (m, 3H),4.75-4.79 (m, 2H), 7.06 (d, J=8.4 Hz, 1H), 7.25 (dd, J=8.4, 2.2 Hz, 1H),7.44 (d, J=2.3 Hz, 1H).

Step D: Preparation of2-(7-(3-Chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid

From tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and2-chloro-4-(chloromethyl)-1-(1,3-difluoropropan-2-yloxy)benzene, thetitle compound was prepared using a similar method to the one describedin Example 1.48, Step B. LCMS m/z=450.1 [M+H]⁺; ¹14 NMR (400 MHz, CDCl₃)δ ppm 2.27-2.36 (m, 1H), 2.67 (dd, J=16.4, 8.4 Hz, 1H), 2.87-2.97 (m,2H), 3.75 (quintet, J=7.4 Hz, 1H), 3.98-4.05 (m, 1H), 4.15 (ddd, J=9.9,8.6, 4.1 Hz, 1H), 4.56-4.69 (m, 3H), 4.75-4.78 (m, 2H), 5.00 (s, 2H),6.12 (s, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 7.06-7.09 (m, 2H), 7.14 (d,J=8.7 Hz, 1H), 7.31 (dd, J=8.4, 2.1 Hz, 1H), 7.51 (d, dr=2.1 Hz, 1H).

Example 1.51 Preparation of2-(7-(4-Methoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 35)

From tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and4-(chloromethyl)-1-methoxy-2-(trifluoromethyl)benzene, the titlecompound was prepared using a similar method to the one described inExample 1.48, Step B. LCMS m/z=420.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 2.31-2.39 (m, 1H), 2.50 (dd, J=16.3, 9.9 Hz, 1H), 2.75 (dd, J=16.3,4.4 Hz, 1H), 2.83-2.93 (m, 1H), 3.59-3.67 (m, 1H), 3.85 (s, 3H),3.95-4.05 (m, 2H), 4.06-4.14 (m, 2H), 5.30 (s, 1H), 6.67-6.74 (m, 2H),6.86 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H),7.43 (d, J=2.0 Hz, 1H).

Example 1.52 Preparation of2-(7-(3-Cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 33)

From tert-butyl2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and5-(chloromethyl)-2-methoxybenzonitrile, the title compound was preparedusing a similar method to the one described in Example 1.16, Step A & B.LCMS m/z=377.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 2.28-2.37 (m, 1H),2.68 (dd, J=16.4, 8.3 Hz, 1H), 2.87-2.98 (m, 2H), 3.73-3.81 (m, 1H),3.94 (s, 3H), 3.99-4.06 (m, 1H), 4.11-4.18 (m, 1H), 5.02 (s, 2H), 6.13(s, 1H), 6.85 (dd, J=8.7, 2.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 7.07 (d,J=2.3 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 7.64 (dd, J=8.6, 2.1 Hz, 1H),7.66 (d, J=2.0 Hz, 1H).

Resolution Via Chiral HPLC

Column: normal phase ChiralPak IA column, 20 mm ID×250 mm L, 5 μmparticle size

Eluent: 30% IPA/hexanes Gradient: Isocratic

Flow: 12 mL/min

Detector: 280 nm

Retention time: 1^(st) enantiomer: 9.6 min; 2^(nd) enantiomer: 18.9 min

Example 1.53 Preparation of 1^(st) Enantiomer of2-(9-Chloro-7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 34)

From the 1^(st) enantiomer (described as the enantiomer isolated andhaving the retention time of 9.6 min per the conditions reported inExample 1.52) of2-(7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid, the title compound was prepared using a similar method to the onedescribed in Example 1.26. LCMS m/z=411.3 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 2.32-2.41 (m, 1H), 2.61 (dd, J=16.8, 10.3 Hz, 1H),2.93-3.01 (m, 1H), 3.31 (dd, J=16.8, 3.9 Hz, 1H), 3.78-3.86 (m, 1H),3.94 (s, 3H), 3.99-4.04 (m, 1H), 4.12-4.19 (m, 1H), 5.05 (s, 2H), 6.88(dd, J=8.8, 2.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H),7.13 (d, J=8.8 Hz, 1H), 7.64 (dd, J=8.6, 2.2 Hz, 1H), 7.68 (d, J=2.1 Hz,1H).

Example 1.54 Preparation of 2^(nd) Enantiomer of2-(9-Chloro-7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticAcid (Compound 34)

From the 2^(nd) enantiomer (described as the enantiomer isolated andhaving the retention time of 18.9 min per the conditions reported inExample 1.52) of2-(7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid, the title compound was prepared using a similar method to the onedescribed in Example 1.26. LCMS m/z=411.2 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 2.32-2.41 (m, 1H), 2.61 (dd, J=16.8, 10.3 Hz, 1H),2.93-3.01 (m, 1H), 3.31 (dd, J=16.8, 3.9 Hz, 1H), 3.78-3.86 (m, 1H),3.94 (s, 3H), 3.99-4.04 (m, 1H), 4.12-4.19 (m, 1H), 5.05 (s, 2H), 6.88(dd, J=8.8, 2.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H),7.13 (d, J=8.8 Hz, 1H), 7.64 (dd, J=8.6, 2.2 Hz, 1H), 7.68 (d, J=2.1 Hz,1H).

Example 2 Homogeneous Time-Resolved Fluorescence (HTRF®) Assay forDirect cAMP Measurement

Compounds were screened for agonists of the S1P1 receptor (e.g., humanS1P1 receptor) using the HTRF® assay for direct cAMP measurement(Gabriel et al., Assay and Drug Development Technologies, 1:291-303,2003) and recombinant CHO-K1 cells stably transfected with S1P1. CHO-K1cells were obtained from ATCC® (Manassas, Va.; Catalog #CCL-61). Anagonist of the S1P1 receptor was detected in the HTRF® assay for directcAMP measurement as a compound which decreased cAMP concentration. HTRF®assay also was used to determine EC₅₀ values for S1P1 receptor agonists.

Principle of the Assay:

HTRF® assay kit was purchased from Cisbio-US, Inc. (Bedford, MA; Catalog#62AM4PEC). The HTRF® assay supported by the kit is a competitiveimmunoassay between endogenous cAMP produced by the CHO-K 1 cells andtracer cAMP labeled with the dye d2. The tracer binding is visualized bya monoclonal anti-cAMP antibody labeled with Cryptate. The specificsignal (i.e., fluorescence resonance energy transfer, FRET) is inverselyproportional to the concentration of unlabeled cAMP in the standard orsample.

Standard Curve:

The fluorescence ratio (665 nm/620 nm) of the standards (0.17 to 712 nMcAMP) included in the assay was calculated and used to generate a cAMPstandard curve according to the kit manufacturer's instructions. Thefluorescence ratio of the samples (test compound or compound buffer) wascalculated and used to deduce respective cAMP concentrations byreference to the cAMP standard curve.

Setup of the Assay:

The HTRF® assay was carried out using a two-step protocol essentiallyaccording to the kit manufacturer's instructions, in 20 μL total volumeper well in 384-well plate format (ProxiPlates; PerkinElmer, Fremont,Calif.; catalog #6008280). To each of the experimental wells wastransferred 1500 recombinant CHO-K1 cells in 5 μL phosphate bufferedsaline containing calcium chloride and magnesium chloride (PBS+;Invitrogen, Carlsbad, Calif.; catalog #14040) supplemented with IBMX(250 μM) and rolipram (20 μM) (phosphodiesterase inhibitors;Sigma-Aldrich, St. Louis, Mo.; catalog #15879 and catalog #R6520,respectively), followed by test compound in 5 μL compound buffer (PBS+supplemented with 10 μL NKH477 (water-soluble forskolin derivative;SignaGen Laboratories, Gaithersburg, Md.; catalog #PKI-NKH477-010)) or 5μL compound buffer. The plate was then incubated at room temperature for1 h. To each well was then added 5 μL cAMP-d2 conjugate in lysis bufferand 5 μL Cryptate conjugate in lysis buffer according to the kitmanufacturer's instructions. The plate was then further incubated atroom temperature for 1 hour, after which the assay plate was read.

Assay Readout:

HTRF® readout was accomplished using a PHERAstar (BMG LABTECH Inc.,Durham, N.C.) or EnVision™ (PerkinElmer, Fremont Calif.) microplatereader.

Certain compounds of the present invention and their correspondingactivity values are shown in Table B.

TABLE B Compound No. EC₅₀ S1P1 (HTRF ®) 4 321 pM 6 239 pM 10 11 pM 115.2 nM 14 6.3 nM

Certain other compounds of the invention had activity values rangingfrom about 11 pM to about 6.3 nM in this assay.

Example 3 Cellular/Functional Ca²⁺Assay for Agonist Activity on S1P3Receptor

A compound of the invention can be shown to have no or substantially noagonist activity on the S1P3 receptor by using in assay a humanneuroblastoma cell line which endogenously expresses S1P3(predominantly), S1P2 and S1P5 receptors, but not S1P1 or S1P4receptors, based on mRNA analysis (Villullas et al., J. Neurosci. Res.,73:215-226, 2003). Of these, S1P3 and S1P2 receptors respond toagonists, such as S1P, with an intracellular calcium increase. No orsubstantially no increase of intracellular calcium in response to a testcompound is indicative of the test compound exhibiting no orsubstantially no agonist activity on the S1P3 receptor. Such an assaycan be performed commercially, e.g. by Caliper LifeSciences (Hopkinton,Mass.).

Assay:

The human neuroblastoma cells are washed and resuspended inphysiological buffer. The cells are then loaded with dye that measuresintracellular calcium. S1P is used as a reference agonist. Afteraddition of S1P or a test compound, fluorescence is measured at 485 nmexcitation/525 nm emission every 2 s for at least 60 s. Calciumionophore A23187 is then added as an internal positive control.

Example 4 Effect of Compounds in Peripheral Lymphocyte Lowering (PLL)Assay

A compound of the invention can be shown to induce peripheral lymphocytelowering (PLL).

A. Mouse PLL Assay.

Animals:

Male BALB/c mice (Charles River Laboratories, Wilmington, Mass.) werehoused four per cage and maintained in a humidity-controlled (40 to 60%)and temperature-controlled (68 to 72° F.) facility on a 12 h:12 hlight/dark cycle (lights on at 6:30 am) with free access to food (HarlanTeklad, Orange, Calif., Rodent Diet 8604) and water. Mice were allowedone week of habituation to the animal facility before testing.

PLL Assay:

Mice were given an oral dose of Compound 2 or dosing vehicle (0.5%methylcellulose) in a total volume of 10 mL/kg. Peripheral blood sampleswere collected at 5 hours post-dose. The mice were anesthetized withisoflurane and blood was collected via cardiac puncture. A complete cellcount (CBC), including lymphocyte count, was obtained using a CELL-DYN®3700 (Abbott Laboratories, Abbott Park, Ill.) instrument. Results arepresented in FIG. 11, in which peripheral blood lymphocyte (PBL) countis shown for the 5 hour group. Reduction of the PBL count by the testcompound in comparison with vehicle is indicative of the test compoundexhibiting activity or inducing peripheral lymphocyte lowering. It isapparent from inspection of FIG. 11 that Compound 2 exhibited activityfor inducing PBL lowering (lymphopenia) in the mouse.

B. Rat PLL Assay.

Animals:

Male Sprague-Dawley rats (Charles River Laboratories, Hollister, Calif.)were housed and maintained in humidity (40 to 60%) and temperature (68to 72° F.) controlled facility on a 12 h:12 h light/dark cycle (lightson at 6:30 am) with free access to food (Harlan Teklad, Orange, Calif.,Rodent Diet 8604) and water. Rats were allowed (approximately) one weekof habituation to the animal facility before testing.

PLL Assay:

Rats were given a 1 mg/kg intravenous dose of the first enantiomerisolated after resolution of compound 12 by HPLC (retention time: 15 minper the conditions reported in Example 1.3), or dosing vehicle (40%hydroxypropyl-cyclodextrin (HPCD)) in a total volume of 1 mL/kg.Peripheral blood samples were collected at 5 h post-dose. Blood wascollected via indwelling catheter. A complete cell count (CBC),including lymphocyte count, was obtained using a CELL-DYN® 3700 (AbbottLaboratories, Abbott Park, Ill.) instrument. Results are presented inFIG. 12, in which peripheral blood lymphocyte (PBL) count is shown forthe 5 hour group. Reduction of the PBL count by the test compound incomparison with vehicle is indicative of the test compound exhibitingactivity or inducing peripheral lymphocyte lowering. It is apparent frominspection of FIG. 12 that the first enantiomer isolated afterresolution of compound 12 by HPLC exhibited activity for inducing PBLlowering (lymphopenia) in the rat.

Similarly, rats were given a 1 mg/kg intravenous dose of the secondenantiomer isolated after resolution of compound 12 by HPLC (retentiontime: 18 min per the conditions reported in Example 1.3), or dosingvehicle (40% hydroxypropyl-cyclodextrin (HPCD)) in a total volume of 1mL/kg. Peripheral blood samples were collected at 5 h post-dose. Bloodwas collected via indwelling catheter. A complete cell count (CBC),including lymphocyte count, was obtained using a CELL-DYN® 3700 (AbbottLaboratories, Abbott Park, Ill.) instrument. Results are presented inFIG. 13, in which peripheral blood lymphocyte (PBL) count is shown forthe 5 hour group. Reduction of the PBL count by the test compound incomparison with vehicle is indicative of the test compound exhibitingactivity or inducing peripheral lymphocyte lowering. It is apparent frominspection of FIG. 13 that the second enantiomer isolated afterresolution of compound 12 by HPLC exhibited activity for inducing PBLlowering (lymphopenia) in the rat.

Example 5 Effect of Compounds on Experimental AutoimmuneEncephalomyelitis (EAE)

A compound of the invention can be shown to have therapeutic efficacy inmultiple sclerosis by showing it to have therapeutic efficacy inexperimental autoimmune encephalomyelitis (EAE), an animal model formultiple sclerosis. In certain exemplary well-established models, EAE isinduced in rodents by injection of myelin oligodendrocyte glycoprotein(MOG) peptide, by injection of myelin basic protein (MBP) or byinjection of proteolipid protein (PLP) peptide.

A. MOG-Induced EAE in Mice.

Animals:

Female C57BL/6 mice (8 to 10 weeks of age at start of study) (JacksonLaboratory, Bar Harbor, Me.) are housed four per cage and maintained ina humidity-controlled (40-60%) and temperature-controlled (68-72° F.)facility on a 12 h:12 h light/dark cycle (lights on at 6:30 am) withfree access to food (Harlan Teklad, Orange, Calif., Rodent Diet 8604)and water. Mice are allowed one week of habituation to the animalfacility before testing.

Induction of EAE:

Mice are immunized subcutaneously, 50 μL per hind flank, with a total of100 μg MOG₃₅₋₅₅ peptide emulsified 1:1 with complete Freund's adjuvantcontaining 4 mg/mL heat-killed Mycobacterium tuberculosis. Mice alsoreceive 200 ng pertussis toxin intraperitoneally on the day ofimmunization and 48 h later.

Clinical Scoring:

Severity of disease symptoms is scored as follows (in increasing orderof severity): 0=normal; 1=limp tail OR hind limb weakness; 2=limp tailAND limb weakness/weakness of 2 or more limbs; 3=severe limb weakness orsingle limb paralysis; 4=paralysis of 2 or more limbs; 5=death.

Drug Treatment:

Mice are dosed orally, with vehicle or a test compound, once a day fromday 3 until day 21. Dosing volume is 5 mL/kg. The test compound is dosedat, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Mice are weigheddaily. Mice are monitored daily from day 7 onward for disease symptoms.After the last dose on day 21, disease progression is monitored dailyfor 2 more weeks. Reduction of the severity of disease symptoms by thetest compound in comparison with vehicle is indicative of the testcompound exhibiting therapeutic efficacy in EAE.

B. PLP-Induced EAE in Mice.

Animals:

Female SJL/J mice (8 to 10 weeks of age at start of study) (JacksonLaboratory, Bar Harbor, Me.) are housed four per cage and maintained ina humidity-controlled (40-60%) and temperature-controlled (68-72° F.)facility on a 12 h:12 h light/dark cycle (lights on at 6:30 am) withfree access to food (Harlan-Teklad Western Res, Orange, Calif., RodentDiet 8604) and water. Mice are allowed one week of habituation to theanimal facility before testing.

Induction of EAE:

Mice are immunized subcutaneously with 100 μg PLP₁₃₉₋₁₅₁ peptideemulsified 1:1 with complete Freund's adjuvant containing 4 mg/mLheat-killed Mycobacterium tuberculosis. Mice also receive 200 ngpertussis toxin intravenously on the day of immunization.

Clinical Scoring:

Severity of disease symptoms is scored as follows (in increasing orderof severity): 0=normal; 1=limp tail OR hind limb weakness; 2=limp tailAND limb weakness/weakness of 2 or more limbs; 3=severe limb weakness orsingle limb paralysis; 4=paralysis of 2 or more limbs; 5=death.

Drug Treatment:

Mice are dosed orally, with vehicle or a test compound, once a day fromday 3 until day 21. Dosing volume is 5 ml/kg. The test compound is dosedat, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Mice are weigheddaily. Mice are monitored daily from day 7 onward for disease symptoms.After the last dose on day 21, disease progression is monitored dailyfor two more weeks.

C. MBP-Induced EAE in Rats.

Animals:

Male Lewis rats (325-375 g at start of study) (Harlan, San Diego,Calif.) are housed two per cage and maintained in a humidity-controlled(30-70%) and temperature-controlled (20-22° C.) facility on a 12 h:12 hlight/dark cycle (lights on at 6:30 A.M.) with free access to food(Harlan-Teklad Western Res., Orange, Calif., Rodent Diet 8604) andwater. Rats are allowed one week of habituation to the animal facilitybefore testing. During the study, rats are weighed daily prior toclinical scoring at 11 am.

Induction of EAE:

Myelin basic protein (MBP; guinea pig) is dissolved in sterile saline ata concentration of 1 mg/ml, and then emulsified 1:1 with completeFreund's adjuvant (1 mg/ml). 50 μL of this emulsion is administered byintraplantar (ipl) injection into both hind paws of each rat, for atotal injected volume of 100 μL per rat and a total dose of 50 μg of MBPper rat.

Clinical Scoring:

Severity of disease symptoms is scored daily after body weighing andbefore drug dosing. Severity of disease symptoms is scored as follows(in increasing order of severity): 0=normal; 1=tail OR limb weakness;2=tail AND limb weakness; 3=severe hind limb weakness or single limbparalysis; 4=loss of tail tone and paralysis of 2 or more limbs;5=death.

Drug Treatment:

Rats are dosed orally, with vehicle or a test compound, 1 hour prior toMBP injection on day 0 and daily thereafter, after clinical scoring, forthe duration of the study. Dosing volume is 5 mL/kg. The test compoundis dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Reduction ofthe severity of disease symptoms by the test compound in comparison withvehicle is indicative of the test compound exhibiting therapeuticefficacy in EAE.

Example 6 Effect of Compounds on Type I Diabetes

A compound of the invention can be shown to have therapeutic efficacy intype I diabetes using an animal model for type I diabetes, such ascyclophosphamide-induced type I diabetes in mice.

Animals:

Baseline blood glucose measurements are taken from 9-10 week old femaleNOD/Ltj mice (Jackson Laboratory, Bar Harbor, Me.) to ensure that theyare normoglycemic (blood glucose is 80-120 mg/dL) prior to initiation ofthe experiment. Blood glucose is measured from tail bleeds using aOneTouch® Ultra® meter and test strips (LifeScan, Milpitas, Calif.).

Cyclophosphamide Induction of Type I Diabetes:

On day 0 and day 14, normoglycemic NOD mice are injectedintraperitoneally with 4 mg cyclophosphamide monohydrate (200 mg/kg)dissolved in 0.9% saline. If mice are diabetic (blood glucose is >250mg/dL), they are not given a booster dose of cyclophosphamide on day 14.

Drug Treatment:

Mice are dosed orally, with vehicle or test compound, once a day fromday 0 until day 25. Compounds are suspended in 0.5% methyl cellulosevehicle using a sonicator to ensure uniform suspension. Mice are weighedtwice weekly and are dosed according to weight. Dosing volume is 5mL/kg. The test compound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kgor 30 mg/kg. Blood glucose is measured twice weekly. After dosing iscompleted at day 25, the mice continue to be monitored and blood glucosemeasurements are taken once a week for 3 weeks. Promotion ofnormoglycemia by the test compound in comparison with vehicle isindicative of the test compound exhibiting therapeutic efficacy in typeI diabetes.

Example 7 Allograft Survival

A compound of the invention can be shown to have therapeutic efficacy inprolonging allograft survival by showing it to have therapeutic efficacyin prolonging, e.g., survival of a skin allograft in an animal model.

Animals:

Female Balbc/mice (6 to 7 weeks of age at start of study) (JacksonLaboratory, Bar Harbor, Me.) are housed four per cage and maintained ina humidity-controlled (40-60%) and temperature-controlled (68-72° F.)facility on a 12 h:12 h light/dark cycle (lights on at 6:30 am) withfree access to food (Harlan Teklad, Orange, Calif., Rodent Diet 8604)and water. Female C57BL/6 mice (8 to 10 weeks of age at start of study)(Jackson Laboratory, Bar Harbor, Me.) are similarly housed andmaintained. Mice are allowed one week of habituation to the animalfacility before testing.

Skin Allograft:

Balbc/J and C57BL/6 mice are used as donors and recipients,respectively, in a model of skin allograft transplantation. DonorBalbc/J mice are anesthetized, and 0.5 cm—diameter full thickness areasof abdominal skin are surgically removed. Skin grafts harvested from theBalbc/J mice are sutured onto the dorsum of anesthetized recipientC57BL/6 mice. Sutured allografts are covered with Vaseline gauze andBolster dressing for 7 days. The allografted mice are divided into 8groups of 8 mice each.

Clinical Scoring:

Skin allografts are inspected and digital images recorded daily untilrejection, which is defined as the first day on which more than 80% ofthe graft is necrotic. Histological analysis of the rejected graft iscarried out on hematoxylin and eosin (H&E)-stained sections. In anoptional related study, on post-transplantation day 5 isolatedlymphocytes from peripheral lymph nodes and spleen are counted andcharacterized for activation markers (e.g., T-cell activation markers)by flow cytometry. Also on day 5, grafts are removed from transplantedrecipients, cut into small fragments, digested with collagenase andsedimented over Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) toisolate graft-infiltrating lymphocytes, which are counted andcharacterized for activation markers (e.g., T-cell activation markers)by flow cytometry. Histological analysis of the graft on day 5 can becarried out on hematoxylin and eosin (H&E)-stained sections.

Drug Treatment:

Mice are dosed orally, with vehicle or test compound, once a day fromthe day of transplantation until the end of the study, e.g. until day14, 21 or 28. Dosing volume is 5 mL/kg. The test compound is dosed at,e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg. Delay of time of rejectionof the skin allograft by the test compound in comparison with vehicle isindicative of the test compound exhibiting therapeutic efficacy inprolonging skin allograft survival.

Example 8 Effect of Compounds on Colitis

A compound of the invention can be shown to have therapeutic efficacy incolitis using an animal model for colitis. Suitable animal models areknown in the art (Boismenu et al., J. Leukoc. Biol., 67:267-278, 2000).A first exemplary animal model for colitis is trinitrobenzenesulfonicacid (TNBS)-induced colitis, which presents clinical andhistopathological findings that resemble those in Crohn's disease(Neurath et al., J. Exp. Med., 182:1281-1290, 1995; Boismenu et al., J.Leukoc. Biol., 67:267-278, 2000). A second exemplary animal model forcolitis is dextran sulfate sodium (DSS)-induced colitis, which presentsclinical and histopathological findings that resemble those inulcerative colitis (Okayasu et al., Gastroenterology, 98:694-702, 1990;Boismenu et al., J. Leukoc. Biol., 67:267-278, 2000). Compounds can becommercially tested for efficacy in at least DSS-induced colitis andTNBS-induced colitis, e.g. by the Jackson Laboratory (Bar Harbor, Me.).

A. Mouse Model for Colitis.

Animals:

Male BALB/c mice (6 weeks of age at start of study) (Jackson Laboratory,Bar Harbor, Me.) are housed four per cage and maintained in ahumidity-controlled (40-60%) and temperature-controlled (68-72° F.)facility on a 12 h:12 h light/dark cycle (lights on at 6:30 am) withfree access to food (Harlan Teklad, Orange Calif., Rodent Diet 8604) andwater. Mice are allowed one week of habituation to the animal facilitybefore testing.

TNBS Induction of Colitis:

Mice are weighed for baseline body weights and fasted later that daybeginning at 6:15 pm just prior to lights-out (day 0). Body weights aretaken again the following morning (day 1) at approximately 7:30 am. Miceare anesthetized with isoflurane prior to induction of colitis. Colitisis induced in the mice by intracolonic injection of about 150 mg/kg TNBSin 50% ethanol (in a volume of 150 μL) using an intubation needle (22 g,1.5 in) inserted completely into the anus with the mouse held by thetail in a vertical position. The mouse is held vertically for 30additional seconds to allow thorough absorption and minimize leakage,after which the mouse is returned to its cage. Mice are then fed,following the preceding approximately 14 hour of fasting. Each morningthereafter, the mice are weighed. In control experiments, mice receive50% ethanol alone using the same protocol.

Drug Treatment:

Drug treatment begins on day 2. Mice are dosed orally, with vehicle or atest compound, once a day from day 2 until the conclusion of theexperiment on, e.g., day 7, 14 or 21. Dosing volume is 5 mL/kg. The testcompound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg.

Clinical Scoring:

Upon conclusion of the experiment, colons are extracted and measured.Mice are euthanized with CO₂ and colon is removed from anus to cecum.Excised colon is measured for entire length, length from anus to end ofinflamed area and length of inflamed (affected) area. Aftermeasurements, colon is cleared of excrement by flushing with saline andthen cut open to clear more thoroughly. Colon is then weighed andpreserved in neutral buffered formalin (NBF; 10% formalin, pH 6.7-7.0).The colon tissue is embedded in paraffin and processed for hematoxylinand eosin (H & E)-stained sections. Severity of disease symptoms isscored histologically from the stained sections as follows: 0=noevidence of inflammation; 1=low level of leukocyte infiltration withinfiltration seen in <10% of high-power fields AND no structuralchanges; 2=moderate leukocyte infiltration with infiltration seen in 10%to 25% of high-power fields AND crypt elongation AND bowel wallthickening that does not extend beyond the mucosal layer AND noulcerations; 3=high level of leukocyte infiltration seen in 25% to 50%of high-power fields AND crypt elongation AND infiltration beyond themucosal layer AND thickening of the bowel wall AND superficialulcerations; 4=marked degree of transmural leukocyte infiltration seenin >50% of high-power fields AND elongated and distorted crypts ANDbowel wall thickening AND extensive ulcerations. Reduction of theseverity of the disease symptoms by the test compound in comparison withvehicle is indicative of the test compound exhibiting therapeuticefficacy in colitis.

B. Rat Model for Colitis.

Animals:

Male Wistar rats (175-200 g at start of study) (Charles RiverLaboratories, Wilmington, Mass.) are housed two per cage and maintainedin a humidity-controlled (40-60%) and temperature-controlled (68-72° F.)facility on a 12 h:12 h light/dark cycle (lights on at 6:30 am) withfree access to food (Harlan Teklad, Orange Calif., Rodent Diet 8604) andwater. Rats are allowed one week of habituation to the animal facilitybefore testing.

TNBS Induction of Colitis:

Rats are weighed for baseline body weights and fasted later that daybeginning at 6:15 pm just prior to lights-out (day 0). Body weights aretaken again the following morning (day 1) at approximately 7:30 am. Ratsare anesthetized with isoflurane prior to induction of colitis. Colitisis induced in the rats by intracolonic injection of about 60 mg/kg TNBSin 50% ethanol (in a volume of 500 μL) using a fabricated intubationneedle (7.5 Fr umbilical catheter and 14 g hub) inserted 8 cm into theanus with the rat held by the tail in a vertical position. The rat isheld vertically for 30 additional s to allow thorough absorption andminimize leakage, after which the rat is returned to its cage. Rats arethen fed, following the preceding approximately 14 h of fasting. Eachmorning thereafter, the rats are weighed. In control experiments, ratsreceive 50% ethanol alone using the same protocol.

Drug Treatment:

Drug treatment begins on day 2. Rats are dosed orally, with vehicle ortest compound, once a day from day 2 until the conclusion of theexperiment on, e.g., day 7, 14 or 21. Dosing volume is 5 mL/kg. Testcompound is dosed at, e.g., 1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg.

Clinical Scoring:

Upon conclusion of the experiment, colons are extracted and measured.Rats are euthanized with CO₂ and colon is removed from anus to cecum.Excised colon is measured for entire length, length from anus to end ofinflamed area, and length of inflamed (affected) area. Aftermeasurements, colon is cleared of excrement by flushing with saline andthen cut open to clear more thoroughly. Colon is then weighed andpreserved in neutral buffered formalin (NBF; 10% formalin, pH 6.7-7.0).The colon tissue is embedded in paraffin and processed for hematoxylinand eosin (H & E)-stained sections. Severity of disease symptoms isscored histologically from the stained sections as follows: 0=noevidence of inflammation; 1=low level of leukocyte infiltration withinfiltration seen in <10% of high-power fields AND no structuralchanges; 2=moderate leukocyte infiltration with infiltration seen in 10%to 25% of high-power fields AND crypt elongation AND bowel wallthickening that does not extend beyond the mucosal layer AND noulcerations; 3=high level of leukocyte infiltration seen in 25% to 50%of high-power fields AND crypt elongation AND infiltration beyond themucosal layer AND thickening of the bowel wall AND superficialulcerations; 4=marked degree of transmural leukocyte infiltration seenin >50% of high-power fields AND elongated and distorted crypts ANDbowel wall thickening AND extensive ulcerations. Reduction of theseverity of the disease symptoms by the test compound in comparison withvehicle is indicative of the test compound exhibiting therapeuticefficacy in colitis.

Example 9 Effects of Compounds on Cardiac Telemetry in the Rat

Animals:

Male Sprague-Dawley rats (250-300 g at time of surgery) are implanted byCharles River Laboratories (Wilmington, Mass.) with cardiac transmittingdevices (Data Sciences PhysioTel C50-PXT) into the peritoneal space,with a pressure-sensing catheter inserted into the descending aorta.Rats are allowed at least one week to recover. Rats are housed inindividual cages and maintained in a humidity-controlled (30-70%) andtemperature-controlled (20-22° C.) facility on a 12 h:12 h light/darkcycle (lights on at 7:00 am) with free access to food (Harlan-Teklad,Orange, Calif., Rodent Diet 8604) and water. Rats are allowed one weekof habituation to the animal facility before testing.

Measurement of Cardiovascular Parameters:

The implanted transmitting devices transmit continuous measurements ofblood pressure (systolic, diastolic, mean arterial, pulse), heart rate,body temperature, and motor activity in freely moving conscious animals.These data are transmitted via radiofrequency to a computer which binthe data into 1 min averages using DataSciences ART software. Telemetryrecording takes place over a 21-h period, starting at noon andcontinuing until 9:00 am the following day. A maximum of eight rats aretested at a time, and the same eight rats are utilized for all treatmentgroups in a within-subject design.

Drug Treatment:

Rats are injected orally with vehicle or compound at 1:00 pm. A fullstudy (vehicle+3 doses) requires four separate testing sessions, whichoccur on Mondays-Tuesdays and Thursdays-Fridays. During each of thetesting sessions, the eight rats are divided into four treatment groupssuch that each group comprises N=2 for any given session. Rats arere-tested in subsequent testing sessions in a crossover design such thatby the end of the four sessions, all animals receive all treatments in apseudo-random order, and each group comprises N=8.

Exemplary Bradycardia Assay:

It is expressly contemplated that the rats can be used to show that acompound of the invention has no or substantially no activity forbradycardia. By way of illustration and not limitation, the rats areadministered vehicle or a test compound and heart rate is then measuredover a 120 min period. No or substantially no reduction of heart rate inresponse to the test compound in comparison with vehicle is indicativeof the test compound exhibiting no or substantially no activity forbradycardia.

Example 10 Effect of Compounds on Arthritis

Female Lewis rats were used in this study. Acclimated animals wereanesthetized with isoflurane and given the first collagen injection (day0). On day 6, they were anesthetized again for the second collageninjection. Collagen was prepared by making a 4 mg/mL solution in 0.01 Nacetic acid. Equal volumes of collagen and incomplete Freund's adjuvantwere emulsified by hand mixing until a bead of this material held itsform when placed in water. Each animal received 300 μL of the mixtureeach time, spread over 3 subcutaneous sites on the back.

Treatment (p.o., q.d., 5 mL/kg dosing volume) began on day 0 andcontinued through day 16 with vehicle or compounds given at 24 hintervals. Rats were weighed on days 0, 3, 6 and 9 through 17 andcaliper measurements of the ankles taken on days 9 through 17.

The second enantiomer isolated after resolution of compound 12 by HPLC(retention time: 18 min per the conditions reported in Example 1.3), wasdosed at 0.3, 1 and 3 mg/kg. It is apparent from inspection of FIG. 14that the second enantiomer isolated after resolution of compound 12 byHPLC exhibited activity for reducing mean ankle diameter in the rat. Areduction in mean ankle diameter in the treated animal compared tovehicle only treated animals is an indication that compound 12 exhibitstherapeutic efficacy in the collagen-induced arthritis assay.

Those skilled in the art will recognize that various modifications,additions, substitutions and variations to the illustrative examples setforth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

1. A compound selected from compounds of Formula (I) andpharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein: m is 1 or 2; n is 1 or 2; Y is N or CR¹; Z is N or CR⁴; W is Nor CR⁵; R^(a) is H or C₁-C₆ alkyl; R¹, R², R³, and R⁴ are eachindependently selected from the group consisting of H, C₁-C₆ alkoxy,C₁-C₆ alkyl, C₁-C₆ alkylamino, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylthio,carboxamide, cyano, C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl, C₁-C₆haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, and heterocyclyl,wherein said C₁-C₆ alkyl and C₁-C₆ alkoxy are each optionallysubstituted with one C₃-C₇ cycloalkyl group; and R⁵ is selected from thegroup consisting of H, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, cyano, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, halogen, heteroaryl, and heterocyclyl.2-22. (canceled)
 23. The compound according to claim 1, selected fromcompounds of Formula (Ia) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein: m is 1 or 2; n is 1 or 2; Y is N or CR¹; Z is N or CR⁴; W is Nor CR⁵; R¹ is H; R² is selected from the group consisting of cyano,C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl; R³ is selected from the groupconsisting of H, C₁-C₆ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; R⁴ isH or cyano; and R⁵ is selected from the group consisting of H, C₁-C₆alkyl, C₃-C₇ cycloalkyl, and halogen.
 24. The compound according toclaim 1, selected from compounds of Formula (Ia) and pharmaceuticallyacceptable salts, solvates, and hydrates thereof:

wherein: m is 1 or 2; n is 1 or 2; Y is N or CR¹; Z is N or CR⁴; W is Nor CR⁵; R¹ is H; R² is selected from the group consisting of cyano,trifluoromethoxy, and trifluoromethyl; R³ is selected from the groupconsisting of H, cyclohexyl, cyclopentyl, isobutyl, and isopropoxy; R⁴is H or cyano; and R⁵ is selected from the group consisting of H, bromo,chloro, cyclobutyl, cyclopropyl, fluoro, iodo, and methyl.
 25. Thecompound according to claim 1, selected from compounds of Formula (Ij)and pharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein: m is 1 or 2; R¹ is H or C₁-C₆ haloalkyl; R² is selected fromthe group consisting of H, C₁-C₆ alkoxy, cyano, C₁-C₆ haloalkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkyl, and halogen; R³ is selected from the groupconsisting of H, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl,carboxamide, cyano, C₃-C₇ cycloalkoxy, C₃-C₇ cycloalkyl, C₁-C₆haloalkoxy, and halogen, wherein said C₁-C₆ alkyl and C₁-C₆ alkoxy areeach optionally substituted with one C₃-C₇ cycloalkyl group; R⁴ isselected from the group consisting of H, cyano, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy; and R⁵ is selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, C₃-C₇ cycloalkyl, halogen, andheteroaryl.
 26. The compound according to claim 1, selected fromcompounds of Formula (Ij) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein: m is 1 or 2; R¹ is H or trifluoromethyl; R² is selected fromthe group consisting of H, chloro, cyano, ethoxy, trifluoromethoxy, andtrifluoromethyl; R³ is selected from the group consisting of H, chloro,carboxamide, cyano, cyclohexyl, cyclohexylmethyl, cyclopentyloxy,cyclopentyl, cyclopropylmethoxy, 1,3-difluoropropan-2-yloxy, ethoxy,fluoromethoxy, isobutyl, isopropoxy, methoxy, and methylsulfonyl; R⁴ isselected from the group consisting of H, cyano, trifluoromethoxy, andtrifluoromethyl; and R⁵ is selected from the group consisting of H,bromo, chloro, cyclobutyl, cyclopropyl, ethyl, fluoro, iodo, methyl,methylsulfonyl, and pyridin-2-yl.
 27. The compound according to claim 1,selected from compounds of Formula (Im) and pharmaceutically acceptablesalts, solvates, and hydrates thereof:

wherein: R² is selected from the group consisting of cyano, C₁-C₆haloalkoxy, and C₁-C₆ haloalkyl; R³ is selected from the groupconsisting of H, C₁-C₆ alkoxy, C₁-C₆ alkyl, and C₃-C₇ cycloalkyl; and R⁵is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, and halogen.
 28. The compound according to claim 1, selectedfrom compounds of Formula (Im) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein: R² is selected from the group consisting of cyano,trifluoromethoxy, and trifluoromethyl; R³ is selected from the groupconsisting of H, cyclohexyl, cyclopentyl, isobutyl, and isopropoxy; andR⁵ is selected from the group consisting of H, bromo, chloro,cyclobutyl, cyclopropyl, fluoro, iodo, and methyl.
 29. The compoundaccording to claim 1, selected from the following compounds andpharmaceutically acceptable salts, solvates, and hydrates thereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-bromo-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-cyclopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-cyclobutyl-7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid; and2-(6-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)aceticacid.
 30. The compound according to claim 1, selected from the followingcompounds and pharmaceutically acceptable salts, solvates, and hydratesthereof:2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-carbamoyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;24744-(cyclohexylmethyl)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-(methylsulfonyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(2,4-bis(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-(1H-pyrazol-1-yl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-(cyclopentyloxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(4-(cyclopropylmethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(4-(fluoromethoxy)-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(3-cyano-4-methoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-methoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-9-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-4-cyclopentylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3,4-diethoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(3-chloro-4-(1,3-difluoropropan-2-yloxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(9-chloro-7-(3-cyano-4-isopropoxybenzyloxy)-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)aceticacid;2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;2-(2-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;2-(2-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;2-(2-(3,4-diethoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid;2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid; and2-(2-(3-cyano-5-(trifluoromethoxy)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)aceticacid.
 31. The compound according to claim 1, wherein the stereochemistryfor the C(1) ring carbon of said compound is R.
 32. The compoundaccording to claim 1, wherein the stereochemistry for the C(1) ringcarbon of said compound is S.
 33. A pharmaceutical compositioncomprising a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 34. A method for treating an S1P1receptor-associated disorder in an individual comprising administeringto said individual in need thereof a therapeutically effective amount ofa compound according to claim
 1. 35. A method for treating an S1P1receptor-associated disorder in an individual comprising administeringto said individual in need thereof a therapeutically effective amount ofa compound according to claim 1, wherein said disorder is selected fromthe group consisting of psoriasis, rheumatoid arthritis, Crohn'sdisease, transplant rejection, multiple sclerosis, systemic lupuserythematosus, ulcerative colitis, type I diabetes, hypertensivenephropathy, glomerulosclerosis, myocardial ischemia-reperfusion injury,and acne.
 36. A method for treating a disorder in an individualcomprising administering to said individual in need thereof atherapeutically effective amount of a compound according to claim 1,wherein said disorder is selected from the group consisting ofpsoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus, ulcerative colitis,type I diabetes, and acne.
 37. A method for treating a disease ordisorder mediated by lymphocytes in an individual comprisingadministering to said individual in need thereof a therapeuticallyeffective amount of a compound according to claim
 1. 38. A method fortreating an autoimmune disease or disorder in an individual comprisingadministering to said individual in need thereof a therapeuticallyeffective amount of a compound according to claim
 1. 39. A method fortreating an inflammatory disease or disorder in an individual comprisingadministering to said individual in need thereof a therapeuticallyeffective amount of a compound according to claim
 1. 40. A method fortreating a microbial or viral infection or disease in an individualcomprising administering to said individual in need thereof atherapeutically effective amount of a compound according to claim 1.41-55. (canceled)
 56. A process for preparing a composition comprisingadmixing a compound according to claim 1 and a pharmaceuticallyacceptable carrier.